Fluorine-containing 1, 4-disubstituted piperidine derivatives

ABSTRACT

In the production of fluorine-containing 1,4-disubstituted piperidine derivatives by the reaction of a carboxylic acid of formula where Ar represents aryl or heteroaryl and R 10  represents C 3  -C 6  cycloalkyl in which up to 4 hydrogen atoms are substituted with fluorine or C 3  -C 6  cycloalkyl having 1 to 2 protected or unprotected hydroxyl or oxo groups, or a reactive derivative thereof, with a piperidine derivative of formula [IV] as defined in the specification, especially useful results are obtained using 4-amino-1-(6-aminopyridin-2-ylmethyl)piperidine or a salt thereof, e.g., trihydrochloride, as the piperidine derivative.

This application is a divisional of Ser. No. 09/903,768 filed Jul. 31,1997, now U.S. Pat. No. 5,948,792.

TECHNICAL FIELD

This invention relates to novel fluorine-containing 1,4-disubstitutedpiperidine derivatives, processes for preparing them, pharmaceuticscontaining them and their use as medicines, especially in the treatmentor prophylaxis of various diseases of the respiratory, urinary anddigestive systems.

BACKGROUND ART

Antagonism to muscarinic receptors are known to cause bronchodilation,gastrointestinal hypanakinesis, gastric hyposecretion, dry mouth,mydriasis, suppression of bladder contraction, hypohidrosis, tachycardiaand the like ["Basic and Clinical Pharmacology", 4th ed., APPLETON &LANGE, pp. 83-92 (1989); Drug News & Perspective, 5(6), pp. 345-352(1992)].

It has been made clear through recent studies that there are at leastthree subtypes of muscarinic receptors; the M₁ receptors being presentmainly in the brain, the M₂ receptors mainly in the heart, and the M₃receptors, on smooth muscles and glandular tissues. Whereas, all of thelarge number of compounds heretofore known to exhibit antagonism tomuscarinic receptors non-selectively antagonize the three subtypes ofmuscarinic receptors. Consequently, attempts to use these compounds astherapeutic or prophylactic agents for diseases of the respiratorysystem have caused undesirable side effects such as dry mouth, nauseaand mydriasis. Still in addition, particularly serious side effectsassociated with the central nervous system, such as dementia,attributable to the M₁ receptors and those associated with the heart,such as tachycardia mediated by the M₂ receptors pose problems and theirsolution is strongly demanded.

We have disclosed, as a drug meeting the demand, 1,4-disubstitutedpiperidine derivatives (see: PCT WO96/33973). However, creation of evenmore excellent drug has been in demand.

An object of the present invention is to create even a better drug thansaid known compounds, whereby to provide pharmaceutics exhibiting highlyselective antagonism to M₃ receptors and minimizing adverse side effectand which, therefore, provide safe and effective pharmaceutics fortreatment or prophylaxis of diseases associated with muscarine M₃receptors, eg., such respiratory diseases as chronic obstructivepulmonary diseases, chronic bronchitis, asthma and rhinitis; digestivediseases such as irritable bowel syndrome, convulsive colitis,diverticulitis and pain accompanying contraction of smooth muscles ofthe digestive system; urinary disorders like urinary incontinence andfrequency in neurogenic pollakiurea, neurogenic bladder, nocturnalenuresis, unstable bladder, cystospasm and chronic cystisis; and motionsickness.

DISCLOSURE OF THE INVENTION

According to the present invention, there are provided novelfluorine-containing 1,4-disubstituted piperidine derivatives of thegeneral formula [I] ##STR1## and pharmaceutically acceptable saltsthereof, wherein:

Ar represents an aryl group or a heteroaryl group having 1 to 2 heteroatoms selected from a group consisting of nitrogen, oxygen and sulfur(any 1 to 3 hydrogen atoms on the ring of said aryl or heteroaryl groupmay be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl,nitro, lower alkoxycarbonyl, halogen, lower alkoxy, amino or loweralkylamino);

R¹ represents C₃ -C₆ cycloalkyl whose any 1-4 hydrogen atoms may besubstituted with fluorine atoms(s);

R² represents C₅ -C₁₅ saturated or unsaturated aliphatic hydrocarbongroups whose any 1 to 6 hydrogen atoms may be substituted with fluorineatom(s), aralkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenylgroup having 1 to 2 hetero atoms selected from a group consisting ofnitrogen, oxygen and sulfur (optionally any 1 to 3 hydrogen atoms on thering in said aralkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenylgroup may be substituted with lower alkyl, trifluoromethyl, cyano,hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, amino orlower alkylamino); and

X stands for 0 or NH.

provided that at least either one of R¹ and R² contains one or morefluorine atoms.

The compounds of the above formula [I] which are provided by the presentinvention have not only potent and selective antagonistic activity formuscarinic M₃ receptors but also little side effect. Furthermore theyexhibit excellent oral activity, duration of action andpharmacokinetics. Hence, they are very useful in the treatment orprophylaxis of diseases such respiratory diseases as chronic obstructivepulmonary diseases, chronic bronchitis, asthma and rhinitis: digestivediseases such as irritable bowel syndrome, convulsive colitis,diverticulitis and pain accompanying contraction of smooth muscles ofthe digestive system: urinary disorders like urinary incontinence andfrequency in neurogenic pollakiurea, neurogenic bladder, nocturnalenuresis, unstable bladder, cystospasm and chronic cystisis: and motionsickness.

Hereinafter the meaning of the technical terms used in the presentspecification are elucidated and the invention is explained in furtherdetails.

"An aryl group (any 1 to 3 hydrogen atoms on the ring in said aryl groupmay be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl,nitro, lower alkoxycarbonyl, halogen, lower alkoxy, amino or loweralkylamino)" signifies a substituted or unsubstituted C₆ -C₁₁ arylgroup, examples of which including unsubstituted phenyl group, naphthylgroup or those containing the above-named substituent(s).

As examples of "a heteroaryl group having 1-2 hetero atoms selected froma group consisting of nitrogen, oxygen and sulfur (any 1 to 3 hydrogenatoms on the ring of said heteroaryl group may be substituted with loweralkyl, trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl,halogen, lower alkoxy, amino or lower alkylamino)", unsubstituted2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 2-thienyl,3-thienyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl,4-pyrazolyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 4-pyridazinyl,2-quinolinyl, 2-benzothienyl and 2-indolyl group; and those which aresubstituted with the above-named substituents can be named.

Also examples of "C₃ -C₆ cycloalkyl whose 1-4 hydrogen atoms may besubstituted with fluorine atom(s)" include: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 1-fluorocyclopropyl, 1-fluorocyclobutyl,1-fluorocyclopentyl, 1-fluorocyclohexyl, 2-fluorocyclopropyl,2-fluorocyclobutyl, 2-fluorocyclopentyl, 2-fluorocyclohexyl,3-fluorocyclobutyl, 3-fluorocyclopentyl, 3-fluorocyclohexyl,4-fluorocyclohexyl, 2,2-difluorocyclopropyl, 2,2-difluorocyclobutyl,2,2-difluorocyclopentyl, 2,2-difluorocyclohexyl, 3,3-difluorocyclobutyl,3,3-difluorocyclopentyl, 3,3-difluorocyclohexyl, 4,4-difluorocyclohexyl,3,3,4,4-tetrafluorocyclopentyl, 3,3,4,4-tetrafluorocyclohexyl,2,3-difluorocyclobutyl, 2,3-difluorocyclopentyl,3,4-difluorocyclopentyl, 2,3-difluorocyclohexyl, 3,4-difluorocyclohexyl,2,2,3,3-tetrafluorocyclobutyl and 2,2,3,3-tetrafluorocyclopentyl groups.

Examples of "C₅ -C₁₅ saturated or unsaturated aliphatic hydrocarbongroups whose any 1 to 6 hydrogen atoms may be substituted with fluorineatoms" include C₅ -C₁₅ straight chain or branched alkyl, alkenyl,alkynyl, cycloalkylidenealkyl; cycloalkylalkyl, cycloalkylalkenyl orcycloalkylalkynyl in which optionally hydrogen atom(s) on the cycloalkylring may be substituted with lower alkyl; and cycloalkenylalkyl orcycloalkenylalkenyl in which optionally hydrogen atom(s) on thecycloalkenyl ring may be substituted with lower alkyl; and those whoseany 1 to 6 hydrogen atom(s) are substituted with fluorine atom(s).

Specific examples of such aliphatic hydrocarbon groups include:

unsubstituted or fluorine-substituted alkyl groups such as2-methylbutyl, 3-methylbutyl, pentyl, neopentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, hexyl, 2-methylhexyl, 3-methylhexyl,4-methylhexyl, 5-methylhexyl, 2,4-dimethylpentyl, 2-ethylhexyl,4,5-dimethylhexyl, 4,4-dimethylpentyl, heptyl, 4-methylheptyl, octyl,nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl,3-fluoromethylbutyl, 1-fluoropentyl, 4-fluoropentyl, 5-fluoropentyl,1,1-difluoropentyl, 4,4-difluoropentyl, 5,5,5-trifluoropentyl,1,1,4,4-tetrafluoropentyl, 1,1,5,5,5-pentafluoropentyl, 1-fluorohexyl,5-fluorohexyl, 6-fluorohexyl, 1,1-difluorohexyl, 5,5-difluorohexyl,6,6,6-trifluorohexyl, 1,1,5,5-tetrafluorohexyl,1,1,6,6,6-pentafluorohexyl, 1-fluoro-4-methylpentyl,2-fluoro-4-methylpentyl, 3-fluoro-4-methylpentyl,4-fluoro-4-methylpentyl, 4-fluoromethylpentyl,1,1-difluoro-4-methylpentyl, 4-trifluoromethylpentyl,5,5,5-trifluoro-4-trifluoromethylpentyl,1,1-difluoro-4-trifluoromethylpentyl, 1,1,5-trifluoro-4-methylpentyl,1-fluoro-4-methylhexyl, 4-fluoro-4-methylhexyl, 5-fluoro-4-methylhexyl,6-fluoro-4-methylhexyl, 1,1-difluoro-4-methylhexyl,5,5-difluoro-4-methylhexyl, 4-trifluoromethylhexyl,6,6,6-trifluoro-4-methylhexyl, 6,6,6-trifluoro-4-trifluoromethylhexyl,1,1-difluoro-4-trifluormethylhexyl and1,1-difluoro-6,6,6-trifluoro-4-methylhexyl;

unsubstituted or fluorine-substituted alkenyl groups such as3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,3-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-2-pentenyl,4-methyl-3-pentenyl, 4-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl,4-hexenyl, 4-methyl-2-hexenyl, 4-methyl-3-hexenyl, 4-methyl-4-hexenyl,5-methyl-2-hexenyl, 5-methyl-3-hexenyl, 5-methyl-4-hexenyl,5-methyl-2-heptenyl, 5-methyl-3-heptenyl, 5-methyl-4-heptenyl,5-methyl-5-heptenyl, 3,4-dimethyl-2-pentenyl, 3,4-dimethyl-3-pentenyl,4,5-dimethyl-2-hexenyl, 4,5-dimethyl-3-hexenyl, 4,5-dimethyl-4-hexenyl,octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl,tetradecenyl, pentadecenyl, 1-fluoro-4-methyl-3-pentenyl,2-fluoro-4-methyl-3-pentenyl, (E)-4-fluoromethyl-3-pentenyl,(Z)-4-fluoromethyl-3-pentenyl, 1,1-difluoro-4-methyl-3-pentenyl,2,2-difluoro-4-methyl-3-pentenyl, (E)-4-trifluoromethyl-3-pentenyl,(Z)-4-trifluoromethyl-3-pentenyl,(E)-1,1-difluoro-4-trifluoromethyl-3-pentenyl,(Z)-1,1-difluoro-4-trifluoromethyl-3-pentenyl,5,5,5-trifluoro-4-trifluoromethyl-3-pentenyl,1-fluoro-4-methyl-2-pentenyl, 4-fluoro-4-methyl-2-pentenyl,4-fluoromethyl-2-pentenyl, 1,1-difuoro-4-methyl-2-pentenyl,4-trifluoromethyl-2-pentenyl, 4-fluoro-1,1-difluoro-4-methyl-2-pentenyl,1,1-difluoro-4-trifluoromethyl-2-pentenyl, 1-fluoro-4-methyl-4-pentenyl,2-fluoro-4-methyl-4-pentenyl, 3-fluoro-4-methyl-4-pentenyl,4-fluoromethyl-4-pentenyl, 1,1-difluoro-4-methyl-4-pentenyl,2,2-difluoro-4-methyl-4-pentenyl, 3,3-difluoro-4-methyl-4-pentenyl,4-trifluoromethyl-4-pentenyl, 1,1-difluoro-4-trifluoromethyl-4-pentenyl,1,1,3,3-tetrafluoro-4-methyl-4-pentenyl, 1-fluoro-4-methyl-3-hexenyl,2-fluoro-4-methyl-3-hexenyl, 4-fluoromethyl-3-hexenyl,6-fluoro-4-methyl-3-hexenyl, 4-trifluoromethyl-3-hexenyl,1,1-difluoro-4-methyl-3-hexenyl, 2,2-difluoro-4-methyl-3-hexenyl,4-trifluoromethyl-3-hexenyl, 5,5-difluoromethyl-3-hexenyl,6,6,6-trifluoro-4-methyl-3-hexenyl,1,1-difluoro-4-trifluoromethyl-3-hexenyl,1,1,-difluoro-6,6,6-trifluoromethyl-3-hexenyl and6,6,6-trifluoro-4-trifluoromethyl-3-hexenyl;

2-pentynyl, 3-pentynyl, 4-pentynyl, 4-methyl-2-pentynyl, octynyl,nonynyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl andpentadecynyl, and those alkynyl groups in which optionally any 1 to 6hydrogen atoms are substituted with fluorine atom(s);

unsubstituted and fluorine-substituted cycloalkylalkyl groups in whichany of hydrogen atom(s) on the cycloalkyl ring may be substituted withlower alkyl, such as cyclopropylethyl, cyclopropylpropyl,cyclopropylbutyl, cyclopropylpentyl, cyclopropylhexyl,cyclopropylheptyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl,cyclobutylbutyl, cyclobutylpentyl, cyclopentylmethyl, cyclopentylethyl,cyclopentylpropyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl,cyclohexylpropyl, cyclohexylbutyl, cycloheptylmethyl, cycloheptylethyl,cycloheptylpropyl, cycloheptylbutyl, cyclooctylmethyl, cyclooctylethyl,cyclooctylpropyl, cyclooctylbutyl, 1-methylcyclopentylmethyl,2-methylcyclopentylmethyl, 3-methylcyclopentylmethyl,1-ethylcyclopentylmethyl, 2-ethylcyclopentylmethyl,3-ethylcyclopentylmethyl, 2-cyclopentylethyl,2-(1-methylcyclopentyl)ethyl, 2-(2-methylcyclopentyl)ethyl,2-(3-methylcyclopentyl)ethyl, 2-(1-ethylcyclopentyl)ethyl,2-(2-ethylcyclopentyl)ethyl, 2-(3-ethylcyclopentyl)ethyl,1-methylcyclohexylmethyl, 2-methylcyclohexylmethyl,3-methyloyclohexylmethyl, 4-methylcyclohexylmethyl,1-ethylcyclohexylmethyl, 2-ethylcyclohexylmethyl,3-ethylcyclohexylmethyl, 4-ethylcyclohexylmethyl, cyclohexylethyl,2-(1-methylcyclohexyl)ethyl, 2-(2-methylcyclohexyl)ethyl,2-(3-methylcyclohexyl)ethyl, 2-(4-methylcyclohexyl)ethyl,2-(1-ethylcyclohexyl)ethyl, 2-(2-ethylcyclohexyl)ethyl,2-(3-ethylcyclohexyl)ethyl, 2-(4-ethylcyclohexyl)ethyl,1-methylcycloheptylmethyl, 2-methylcycloheptylmethyl,3-methylcycloheptylmethyl, 4-methylcycloheptylmethyl,1-ethylcycloheptylmethyl, 2-ethylcycloheptylmethyl,3-ethylcycloheptylmethyl, 4-ethylcycloheptylmethyl, 2-cycloheptylethyl,2-(1-methylcycloheptyl)ethyl, 2-(2-methylcycloheptyl)ethyl,2-(3-methylcycloheptyl)ethyl, 2-(4-methylcycloheptyl)ethyl,2-(1-ethylcycloheptyl)ethyl, 2-(2-ethylcycloheptyl)ethyl,2-(3-ethylcycloheptyl)ethyl, 2-(4-ethylcycloheptyl)ethyl,1-methylcyclooctylmethyl, 2-methylcyclooctylmethyl,3-methylcyclooctylmethyl, 4-methylcyclooctylmethyl,5-methylcyclooctylmethyl, 1-ethylcyclooctylmethyl,2-ethylcyclooctylmethyl, 3-ethylcyclooctylmethyl,4-ethylcyclooctylmethyl, 5-ethylcyclooctylmethyl,2-(1-methylcyclooctyl)ethyl, 2-(2-methylcyclooctyl)ethyl,2-(3-methylcyclooctyl)ethyl, 2-(4-methylcyclooctyl)ethyl,2-(5-methylcyclooctyl)ethyl, 2-(1-ethylcyclooctyl)ethyl,2-(2-ethylcyclooctyl)ethyl, 2-(3-ethylcyclooctyl)ethyl,2-(4-ethylcyclooctyl)ethyl and 2-(5-ethylcyclooctyl)ethyl,1-fluoro-1-cyclohexylmethyl, 2-fluorocyclohexylmethyl,3-fluorocyclohexylmethyl, 4-fluorocyclohexylmethyl,1,1-difluoro-1-cyclohexylmethyl, 2,2-difluorocyclohexylmethyl,3,3-difluorocyclohexylmethyl, 4,4-difluorocyclohexylmethyl,1-fluoro-1-cycloheptylmethyl, 2-fluorocycloheptylmethyl,3-fluorocycloheptylmethyl, 4-fluorocycloheptylmethyl,1,1-difluoro-1-cycloheptylmethyl, 2,2-difluorocycloheptylmethyl,3,3-difluorocycloheptylmethyl, 4,4-difluorocycloheptylmethyl,1-fluoro-1-(3-methylcyclohexyl)methyl,2-fluoro-3-methylcyclohexylmethyl, 3-fluoro-3-methylcyclohexylmethyl,4-fluoro-3-methylcyclohexylmethyl,1,1-difluoro-1-(3-methylcyclohexyl)methyl,2,2-difluoro-3-methylcyclohexylmethyl,3-trifluoromethylcyclohexylmethyl,4,4-difluoro-3-methylcyclohexylmethyl, 1-fluoro-2-cyclopentylethyl,2-(2-fluorocyclopentyl)ethyl, 2-(3-fluorocyclopentyl)ethyl,1,1-difluoro-2-cyclopentylethyl, 2-(2,2-difluorocyclopentyl)ethyl,2-(3,3-difluorocyclopentyl)ethyl,1,1-difluoro-2-(2,2-difluorocyclopentyl)ethyl and1,1-difluoro-2-(3,3-difluorocyclopentyl)ethyl;

cycloalkylidenealkyl groups such as cyclopropylideneethyl,cyclopropylidenepropyl, cyclopropylidenebutyl, cyclopropylidenepentyl,cyclobutylideneethyl, cyclobutylidenepropyl, cyclobutylidenebutyl,cyclobutylidenepentyl, cyclopentylideneethyl, cycIopentylidenepropyl,cyclopentylidenebutyl, cyclopentylidenepentyl, cyclohexylideneethyl,cyclohexylidenepropyl, cyclohexylidenebutyl, cyclohexylidenepentyl,cycloheptylideneethyl, cycloheptylidenepropyl, cycloheptylidenebutyl,cycloheptylidenepentyl, cyclooctylideneethyl, cyclooctylidenepropyl,cyclooctylidenebutyl and cyclooctylidenepentyl, and thosecycloalkylidene alkyl groups in which optionally any 1 to 6 hydrogenatoms are substituted with fluorine atom(s);

cycloalkylalkenyl groups such as cyclopropylpropenyl,cyclopropylbutenyl, cyclopropylpentenyl, cyclopropylhexenyl,cyclopropylheptenyl, cyclobutylpropenyl, cyclobutylbutenyl,cyclobutylpentenyl, cyclopentylpropenyl, cyclopentylbutenyl,cyclopentylpentenyl, cyclohexylpropenyl, cyclohexylbutenyl,cyclohexylpentenyl, cycloheptylpropenyl and cyclooctylpropenyl, andthose cycloalkylalkenyl groups in which optionally any 1 to 6 hydrogenatoms are substituted with fluorine atom(s);

cycloalkylalkynyl groups such as cyclopropylpropynyl,cyclopropylbutynyl, cyclopropylpentynyl, cyclopropylhexynyl,cyclopropylheptynyl, cyclobutylpropynyl, cyclobutylbutynyl,cyclobutylpentynyl, cyclopentylpropynyl, cyclopentylbutynyl,cyclopentylpentynyl, cyclohexylpropynyl, cyclohexylbutynyl andcyclohexylpentynyl, and those cycloalkylalkynyl groups in whichoptionally any 1 to 6 hydrogen atoms are substituted with fluorineatom(s);

cycloalkenylalkyl groups in which any optional hydrogen atom(s) on thecycloalkenyl ring may be replaced by a lower alkyl group(s), such ascyclopropenylethyl, cyclopropenylpropyl, cyclopropenylbutyl,cyclopropenylpentyl, cyclopropenylhexyl, cyclopropenylheptyl,cyclobutenylmethyl, cyclobutenylethyl, cyclobutenylpropyl,cyclopentenylmethyl, cyclohexenylmethyl, cyclohexenylethyl,cycloheptenylmethyl, cycloheptenylethyl, cyclooctenylmethyl,cyclooctenylethyl, (1-methyl-2-cyclopentenyl)methyl,(1-methyl-3-cyclopentenyl)methyl, (2-methyl-1-cyclopentenyl)methyl,(2-methyl-2-cyclopentenyl)methyl, (2-methyl-3-cyclopentenyl)methyl,(5-methyl-2-cyclopentenyl)methyl, (5-methyl-1-cyclopentenyl)methyl,(3-methyl-1-cyclopentenyl)methyl, (3-methyl-2-cyclopentenyl)methyl,(3-methyl-3-cyclopentenyl)methyl, (4-methyl-2-cyclopentenyl)methyl,(4-methyl-1-cyclopentenyl)methyl, (1-methyl-2-cyclohexenyl)methyl,(1-methyl-3-cyclohexenyl)methyl, (2-methyl-1-cyclohexenyl)methyl,(2-methyl-2-cyclohexenyl)methyl, (2-methyl-3-cyclohexenyl)methyl,(6-methyl-3-cyclohexenyl)methyl, (6-methyl-2-cyclohexenyl)methyl,(6-methyl-1-cyclohexenyl)methyl, (3-methyl-1-cyclohexenyl)methyl,(3-methyl-2-cyclohexenyl)methyl, (3-methyl-3-cyclohexenyl)methyl,(5-methyl-3-cyclohexenyl)methyl, (5-methyl-2-cyclohexenyl)methyl,(5-methyl-1-cyclohexenyl)methyl, (4-methyl-1-cyclohexenyl)methyl,(4-methyl-2-cyclohexenyl)methyl, (4-methyl-3-cyclohexenyl)methyl,(1-methyl-2-cycloheptenyl)methyl, (1-methyl-3-cycloheptenyl)methyl,(1-methyl-4-cycloheptenyl)methyl, (2-methyl-1-cycloheptenyl)methyl,(2-methyl-2-cycloheptenyl)methyl, (2-methyl-3-cycloheptenyl)methyl,(2-methyl-4-cycloheptenyl)methyl, (7-methyl-3-cycloheptenyl)methyl,(7-methyl-2-cycloheptenyl)methyl, (7-methyl-1-cycloheptenyl)methyl,(3-methyl-1-cycloheptenyl)methyl, (3-methyl-2-cycloheptenyl)methyl,(3-methyl-3-cycloheptenyl)methyl, (3-methyl-4-cycloheptenyl)methyl,(6-methyl-3-cycloheptenyl)methyl, (6-methyl-2-cycloheptenyl)methyl,(6-methyl-1-cycloheptenyl)methyl, (4-methyl-1-cycloheptenyl)methyl,(4-methyl-2-cycloheptenyl)methyl, (4-methyl-3-cycloheptenyl)methyl,(4-methyl-4-cycloheptenyl)methyl, (5-methyl-3-cycloheptenyl)methyl,(5-methyl-2-cycloheptenyl)methyl, (5-methyl-1-cycloheptenyl)methyl,(1-methyl-2-cyclooctenyl)methyl, (1-methyl-3-cyclooctenyl)methyl,(1-methyl-4-cyclooctenyl)methyl, (2-methyl-1-cyclooctenyl)methyl,(2-methyl-2-cyclooctenyl)methyl, (2-methyl-3-cyclooctenyl)methyl,(2-methyl-4-cyclooctenyl)methyl, (8-methyl-4-cyclooctenyl)methyl,(8-methyl-3-cyclooctenyl)methyl, (8-methyl-2-cyclooctenyl)methyl,(8-methyl-1-cyclooctenyl)methyl, (3-methyl-1-cyclooctenyl)methyl,(3-methyl-2-cyclooctenyl)methyl, (3-methyl-3-cyclooctenyl)methyl,(3-methyl-4-cyclooctenyl)methyl, (7-methyl-4-cyclooctenyl)methyl,(7-methyl-3-cyclooctenyl)methyl, (7-methyl-2-cyclooctenyl)methyl,(7-methyl-1-cyclooctenyl)methyl, (4-methyl-1-cyclooctenyl)methyl,(4-methyl-2-cyclooctenyl)methyl, (4-methyl-3-cyclooctenyl)methyl,(4-methyl-4-cyclooctenyl)methyl, (6-methyl-4-cyclooctenyl)methyl,(6-methyl-2-cyclooctenyl)methyl, (6-methyl-1-cyclooctenyl)methyl,(5-methyl-1-cyclooctenyl)methyl, (5-methyl-2-cyclooctenyl)methyl,(5-methyl-3-cyclooctenyl)methyl and (5-methyl-4-cyclooctenyl)methyl, andthose cycloalkenylalkyl groups in which optionally any 1 to 6 hydrogenatoms are substituted with fluorine atom(s); and

cycloalkenylalkenyl groups in which any of hydrogen atoms on thecycloalkenyl ring may be substituted with lower alkyl such ascyclopropenylpropenyl, cyclopropenylbutenyl, cyclobutenylbutenyl,cyclopentenylpropenyl, cyclopentenylbutenyl, cyclopropenylpentenyl,cyclopropenylhexenyl, cyclopropenylheptenyl, cyclobutenylpropenyl,cyclohexenylpropenyl and cyclohexenylbutenyl, and thosecycloalkenylalkenyl groups in which optionally any 1 to 6 hydrogen atomsare substituted with fluorine atom(s).

"Aralkyl (optionally any 1 to 3 hydrogen atoms on the ring in thearalkyl group may be substituted with lower alkyl, trifluoromethyl,cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy,amino or lower alkylamino)" signifies unsubstituted or substituted C₇-C₁₂ aralkyl groups. As their examples, unsubstituted benzyl, phenethyl,phenylpropyl and naphthylmethyl, and those substituted with above-listedsubstituents may be named.

"Arylalkenyl (optionally any 1-3 hydrogen atoms on the ring in thearylalkenyl group may be substituted with lower alkyl, trifluoromethyl,cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy,amino or lower alkylamino)" signifies unsubstituted or substituted C₈-C₁₂ arylalkenyl groups, examples of which include unsubstitutedphenylpropenyl and naphthylpropenyl, and those substituted withabove-listed substituents.

Examples of "heteroarylalkyl having 1 to 2 hetero atoms selected from agroup consisting of nitrogen, oxygen and sulfur (optionally any 1-3hydrogen atoms on the ring in the heteroarylalkyl group may besubstituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro,lower alkoxycarbonyl, halogen, lower alkoxy, amino or lower alkylamino)"include unsubstituted 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-thiazolylmethyl, 2-thienylmethyl, 3-thienylmethyl, 1-imidazolylmethyl,2-imidazolylmethyl, 3-pyrazolylmethyl, 4-pyrazolylmethyl, 2-furylmethyl,3-furylmethyl, 2-pyrrolylmethyl, 3-pyrrolylmethyl, 2-pyrimidinylmethyl4-pyrimidinylmethyl, 5-pyrimidinylmethyl, pyrazinylmethyl,3-pyridazinylmethyl, 4-pyridazinylmethyl, 3-quinolylmethyl,4-quinolylmethyl, 5-quinolylmethyl, 6-quinolylmethyl, 7-quinolylmethyl,8-quinolylmethyl, 1-isoquinolylmethyl, 3-isoquinolylmethyl,4-isoquinolylmethyl, 5-isoquinolylmethyl, 6-isoquinolylmethyl,7-isoquinolylmethyl, 8-isoquinolylmethyl, 2-benzothienylmethyl,3-benzothienylmethyl, 4-benzothienylmethyl, 5-benzothienylmethyl,6-benzothienylmethyl, 7-benzothienylmethyl, 2-indolylmethyl,3-indolylmethyl, 4-indolylmethyl, 5-indolylmethyl, 6-indolylmethyl,7-indolylmethyl, 2-benzimidazolylmethyl, 4-benzimidazolylmethyl,5-benzimidazolylmethyl, 2-benzothiazolylmethyl, 4-benzothiazolylmethyl,5-benzothiazolylmethyl, 6-benzothiazolylmethyl, 7-benzothiazolylmethyl,2-benzoxazolylmethyl, 4-benzoxazolylmethyl, 5-benzoxazolylmethyl,6-benzoxazolylmethyl, 7-benzoxazolylmethyl, 2-benzofuranylmethyl,3-benzofuranylmethyl, 4-benzofuranylmethyl, 5-benzofuranylmethyl,6-benzofuranyImethyl, 7-benzofuranylmethyl, 2-pyridylethyl,2-pyridylpropyl, 3-pyridylethyl, 4-pyridylethyl, 2-thiazolylethyl,2-thienylethyl, 3-thienylethyl, 1-imidazolylethyl, 2-imidazolylethyl,3-pyrazolylethyl, 4-pyrazolylethyl, 2-furylethyl, 3-furylethyl,2-pyrrolylethyl, 3-pyrrolylethyl, 2-pyrimidinylethyl,4-pyrimidinylethyl, 5-pyrimidinylethyl, pyrazinylethyl,3-pyridazinylethyl, 4-pyridazinylethyl, 2-quinizylethyl,2-benzothienylethyl, 3-benzothienylethyl, 4-benzothienylethyl,5-benzothienylethyl, 6-benzothienylethyl, 7-benzothienylethyl,2-indolylethyl, 3-indolylethyl, 4-indolylethyl, 5-indolylethyl,6-indolylethyl, 7-indolylethyl, 2-benzimidazolylethyl,4-benzimidazolylethyl, 5-benzimidazolylethyl, 2-benzothiazolylethyl,4-benzothiazolylethyl, 5-benzothiazolylethyl, 6-benzothiazolylethyl,7-benzothiazolylethyl, 2-benzoxazolylethyl, 4-benzoxazolylethyl,5-benzoxazolylethyl, 6-benzoxazolylethyl, 7-benzoxazolylethyl,2-benzofuranylethyl, 3-benzofuranylethyl, 4-benzofuranylethyl,5-benzofuranylethyl, 6-benzofuranylethyl and 7-benzofuranylethyl, andthose which are substituted with above-listed substituents.

As examples of "heteroarylalkenyl having 1-2 hetero atoms selected fromthe group consisting of nitrogen, oxygen and sulfur (any 1 to 3 hydrogenatoms on the ring of said heteroarylalkenyl group may be substitutedwith lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro, loweralkoxycarbonyl, halogen, lower alkoxy, amino or lower alkylamino)",unsubstituted 2-pyridylpropenyl, 3-pyridylpropenyl, 4-pyridylpropenyl,2-thiazolyipropenyl, 2-thienylpropenyl, 3-thienylpropenyl,1-imidazolylbutenyl, 2-imidazolylpropenyl, 3-pyrazolylpropenyl,4-pyrazolyipropenyl, 2-furylpropenyl, 3-furylpropenyl,2-pyrrolylpropenyl, 3-pyrrolylpropenyl, 2-pyrimidinylpropenyl,4-pyrimidinylpropenyl, 5-pyrimidinylpropenyl, pyrazinylpropenyl,3-pyridazinylpropenyl, 4-pyridazinylpropenyl, 2-quinidylpropenyl,2-benzothienylpropenyl and 2-indolylpropenyl, and those substituted withabove-named substituents may be named.

"Halogen" include fluorine, chlorine, bromine and iodine.

"Lower alkyl" signifies C₁ -C₆ straight chain or branched alkyl groups,for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, t-butyl, pentyl, isopentyl, hexyl and isohexyl groups.

"Lower alkoxy" signifies C₁ -C₆ straight chain or branched alkoxygroups, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,sec-butoxy, isobutoxy, t-butoxy, pentyloxy, isopentyloxy, hexyloxy andisohexyloxy groups.

"Lower alkoxycarbonyl" signifies C₁ -C₇ straight chain or branchedalkoxycarbonyl groups, for example, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl,isobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl,isopentyloxycarbonyl, hexyloxycarbonyl and isohexyloxycarbonyl groups.

"Aralkyloxycarbonyl" signifies C₇ -C₁₀ aralkyloxycarbonyl groups, forexample, benzyloxycarbonyl and phenethyloxycarbonyl groups.

"Lower alkylamino" signifies C₁ -C₆ straight chain or branchedalkylamino groups, for example, methylamino, ethylamino, propylamino,isopropylamino, butylamino, sec-butylamino, t-butylamino, pentylamino,isopentylamino, hexylamino, isohexylamino, dimethylamino, diethylaminoand dipropylamino groups.

"Protected hydroxyl groups" signify hydroxyl groups which are protectedwith acyl such as acetyl, alkylsilyl such as trimethylsilyl andt-butyldimethylsilyl, aralkyl such as benzyl and trityl, ether groupsuch as methoxymethyl, and in the form of alkylideneketal such asisopropylideneketal.

"Protected oxo groups" signify oxo groups which are protected in theform of acetal or ketal such as ethylene ketal, trimethylene ketal anddimethyl ketal.

"Protected amino or lower alkylamino groups" signify amino or loweralkylamino groups which are protected with, for example, aralkyl groupssuch as benzyl, p-methoxybenzyl, p-nitrobenzyl, benzhydryl and trityl;lower alkanoyl groups such as formyl, acetyl and propionyl; arylalkanoylgroups such as phenylacetyl and phenoxyacetyl; lower alkoxycarbonylgroups such as methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl andt-butoxycarbonyl; alkenyloxycarbonyl groups such as2-propenyloxycarbonyl; aralkyloxycarbonyl groups such asbenzyloxycarbonyl and p-nitrobenzyloxycarbonyl, and lower alkylsilylgroups such as trimethylsilyl and t-butyldimethylsilyl. In particular,amino or lower alkylamino groups which are protected witht-butoxycarbonyl and benzyloxycarbonyl groups are preferred.

Also "deprotection" signifies removal of protective groups by the meansconventionally used in the field of organic chemistry, such ashydrolysis, hydrogenolysis and the like.

Referring to the general formula [I],

(1) Ar represents an aryl group or a heteroaryl group having 1 to 2hetero atoms selected from a group consisting of nitrogen, oxygen andsulfur (any 1 to 3 hydrogen atoms on the ring of said aryl or heteroarylgroup may be substituted with lower alkyl, trifluoromethyl, cyano,hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, amino orlower alkylamino). In particular, unsubstituted phenyl or substitutedphenyl having above-named substituents are preferred.

(2) R¹ is a C₃ -C₆ cycloalkyl which may have 1 to 4 fluorine atoms onthe ring; cyclobutyl, cyclopentyl, cyclohexyl, 2-fluorocyclobutyl,3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl,2-fluorocyclopentyl, 3-fluorocyclopentyl, 2,2-difluorocyclopentyl,3,3-difluorocyclopentyl, 2,2,3,3-tetrafluorocyclopentyl,3,3,4,4-tetrafluorocyclopentyl, 2-fluorocyclohexyl, 3-fluorocyclohexyl,4-fluorocyclohexyl, 2,2-difluorocyclohexyl, 3,3-difluorocyclohexyl and4,4-difluorocyclohexyl being preferred.

Of these, particularly 2-fluorocyclobutyl, 3-fluorocyclobutyl,2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl, 2-fluorocyclopentyl,3-fluorocyclopentyl, 2,2-difluorocyclopentyl, 3,3-difluorocyclopentyl,2,2,3,3-tetrafluorocyclopentyl, 3,3,4,4-tetrafluorocyclopentyl,2-fluorocyclohexyl, 3-fluorocyclohexyl, 4-fluorocyclohexyl,2,2-difluorocyclohexyl, 3,3-difluorocyclohexyl and4,4-difluorocyclohexyl are preferred. 3,3-Difluorocyclopentyl is thebest preferred.

(3) X represents 0 or NH, NH being the preferred.

(4) R² represents C₅ -C₁₅ saturated or unsaturated aliphatic hydrocarbongroups whose any 1 to 6 hydrogen atoms may be substituted with fluorineatom(s), aralkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenylgroup having 1 to 2 hetero atoms selected from a group consisting ofnitrogen, oxygen and sulfur (optionally any 1 to 3 hydrogen atoms on thering in said aralkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenylgroup may be substituted with lower alkyl, trifluoromethyl, cyano,hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, amino orlower alkylamino). Of these, the groups expressed by the followingformula [II], in which any 1 to 6 hydrogen atoms may be substituted withfluorine atom(s), ##STR2## [in which Q represents methylene, ethylene,trimethylene or tetramethylene;

R^(a) and R^(c) each represents a hydrogen atom or are combined to forma single bond; and

R^(b), R^(d) and R^(e) may be the same or different and each representsa hydrogen atom, a lower alkyl group, C₃ -C₈ cycloalkyl or cycloalkenyl,or R^(b) and R^(d), or R^(d) and R^(e) together form each a C₃ -C₈cycloalkyl or cycloalkenyl],

benzyl, phenethyl, phenylpropyl, phenylpropenyl, 2-pyridylmethyl,2-pyridylethyl, 2-pyridylpropyl, 3-pyridylmethyl, 4-pyridylmethyl,2-thiazolylmethyl, 2-thienylmethyl, 3-thienylmethyl, 1-imidazolylmethyl,2-imidazolylmethyl, 4-imidazolylmethyl, 2-furylmethyl, 3-furylmethyl,2-pyrrolylmethyl, 3-pyrrolylmethyl (any 1 to 3 hydrogen atoms on thering of said benzyl, phenethyl, phenylpropyl, phenylpropenyl orheteroarylalkyl group may be substituted with lower alkyl,trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen,lower alkoxy, amino or lower alkylamino) are preferred.

In particular, 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl,3-furylmethyl, 2-pyridylmethyl or benzyl (any 1-3 hydrogen atoms on thering in the thienylmethyl, furylmethyl, pyridylmethyl or benzyl groupmay be substituted with lower alkyl, trifluoromethyl, cyano, hydroxyl,nitro, lower alkoxycarbonyl, halogen, amino, lower alkylamino or loweralkoxy) are preferred, inter alia, 6-aminopyridin-2-ylmethyl group ispreferred.

According to the manner of substitution, the compounds of the presentinvention may exist in the form of stereoisomers such as opticalisomers, diastereoisomers and geometrical isomers. It is to beunderstood that the compounds of the present invention also include allsuch stereoisomers and mixtures thereof.

Moreover, the compounds of the present invention may exist in the formof pharmaceutically acceptable salts. Such salts include inorganic acidsalts such as hydrochlorides, sulfates, nitrates, phosphates andperchlorates; organic carboxylic acid salts such as maleates, fumarates,succinates, tartrates, citrates and ascorbates; organic sulfonic acidsalts such as methanesulfonates, isethionates, benzenesulfonates andp-toluenesulfonates; and the like.

The compounds of the above general formula [I] in accordance with thepresent invention can be prepared, for example, by:

(a) reacting a carboxylic acid of the general formula [III] ##STR3##[wherein Ar represents an aryl group or a heteroaryl group having 1 to 2hetero atoms selected from a group consisting of nitrogen, oxygen andsulfur (any 1 to 3 hydrogen atoms on the ring of said aryl or heteroarylgroup may be substituted with lower alkyl, trifluoromethyl, cyano,hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy, amino orlower alkylamino); and R¹⁰ represents a C₃ -C₆ cycloalkyl in which any 1to 4 hydrogen atoms may be substituted with fluorine atom(s) or a C₃ -C₆cycloalkyl having 1 to 2 protected or unprotected hydroxyl or oxogroup(s)]

or a reactive derivative thereof with a compound of the general formula[IV] ##STR4## [wherein R²⁰ represents a C₅ -C₁₅ saturated or unsaturatedaliphatic hydrocarbon group in which any 1 to 6 hydrogen atoms may besubstituted with fluorine atom(s), C₁₅ -C₁₅ saturated or unsaturatedaliphatic hydrocarbon group having 1-2 protected or unprotected hydroxylor oxo group(s), aralkyl, arylalkenyl, heteroarylalkyl orheteroarylalkenyl group having 1 to 2 hetero atoms selected from a groupconsisting of nitrogen, oxygen and sulfur (optionally any 1 to 3hydrogen atoms on the ring in said aralkyl, arylalkenyl, heteroarylalkylor heteroarylalkenyl group may be substituted with lower alkyl,trifluoromethyl, cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen,lower alkoxy, unprotected or protected amino, unprotected or protectedlower alkylamino or aralkyloxycarbonyl group) and X stands for NH or 0];

and when either R¹⁰ or R²⁰ has unprotected or protected 1 to 2 hydroxylor oxo group(s) converting said hydroxyl or oxo groups to fluorineatom(s) either as they are or after removing the protective group(s);when R¹⁰ or R²⁰ has protected amino or protected lower alkylaminogroup(s), removing the protective group(s); and when R¹⁰ or R²⁰ haslower alkoxycarbonyl or aralkyloxycarbonyl, converting the same toamino; or

(b) reacting a carboxylic acid of the above general formula [III] or areactive derivative thereof with a compound of the general formula [V]##STR5## [wherein E is a protective group for the imino group, and X isas defined above]

or a salt thereof; deprotecting the resulting compound of the generalformula [VI] ##STR6## [wherein Ar, R¹⁰, X and E are as definedabove]thereafter reacting the same with a compound of the generalformula [VII]

    R.sup.20 --L                                               [VII]

[wherein L represents a leaving group, and R²⁰ is as defined above]

in the presence of a base, if necessary, and again if necessaryconducting a conversion reaction of R¹⁰ and R²⁰ similar to the above; or

(c) deprotecting a compound of the above general formula [VI] andsubjecting it to a reductive alkylation reaction with a compound of thegeneral formula [VIII]

    R.sup.21 --CHO                                             [VIII]

[wherein R²¹ represents a C₄ -C₁₄ saturated or unsaturated aliphatichydrocarbon group in which any 1 to 6 hydrogen atom(s) may besubstituted with fluorine atom(s), C₄ -C₁₄ saturated or unsaturatedaliphatic hydrocarbon group having unprotected or protected 1 to 2hydroxyl or oxo group(s), aryl, aralkyl, arylalkenyl or heteroaryl,heteroarylalkyl or heteroarylalkenyl having 1 to 2 hetero atoms selectedfrom a group consisting of nitrogen, oxygen and sulfur (optionally any1-3 hydrogen atoms on the ring in said aryl, aralkyl, arylalkenyl,heteroaryl, heteroarylalkyl or heteroarylalkenyl group may besubstituted with lower alkyl, trifluoromethyl, cyano, hydroxyl, nitro,lower alkoxycarbonyl, halogen, lower alkoxy, unprotected or protectedamino, unprotected or protected lower alkylamino oraralkyloxycarbonyl)],

and if necessary conducting the conversion reaction of R¹⁰ and R²¹similar to the foregoing.

In the above formula [VII], "leaving groups" represented by L include,for example, halogen atoms such as chlorine, bromine and iodine;alkylsulfonyloxy groups such as methanesulfonyloxy; and arylsulfonyloxygroups such as p-toluenesulfonyloxy.

In the above formulae [V] and [VI], "protective groups for the iminogroup" represented by E signify similar protective groups to those foramino as above.

In the above-described process variant (a), a carboxylic acid of formula[III] is reacted with a compound of formula [IV] or a salt thereof inthe presence of a suitable condensing agent. Thus, there is obtained acoupled compound of the general formula [IX] ##STR7## [wherein Ar, R¹⁰,X and R²⁰ are as defined above].

The carboxylic acid of formula [III] used as a starting material in theabove condensation reaction can be prepared, for example, by the methodas described in Referential Examples.

The condensing agent to be used in the above-described reaction may beany of those which are commonly used in the field of organic syntheticchemistry for condensation reactions of carboxyl groups with hydroxyl oramino groups, and examples thereof includeN,N'-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, diphenylphosphoryl azideand dipyridyl disulfide-triphenylphosphine. Of these,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide is preferred.

Use rate of these condensing agents are subject to no criticallimitation, while normally it may be within a range of 1 to 5equivalents, preferably 1 to 2 equivalents, per mole of the compound offormula [III].

If necessary, the above-described condensation reaction may be carriedout in the presence of a base. Bases which can be used for this purposeinclude, for example, aliphatic tertiary amines such as triethylamineand diisopropylethylamine; and aromatic amines such as pyridine,4-dimethylaminopyridine, quinoline. 4-Dimethylaminopyridine isparticularly preferred.

The condensation reaction is preferably carried out in an inert solvent.Suitable inert organic solvents include, for example, diethyl ether,tetrahydrofuran, N,N-dimethylformamide, dioxane, benzene, toluene,chlorobenzene, methylene chloride, chloroform, carbon tetrachloride,dichloroethane, trichloroethylene and mixtures of the foregoingsolvents. Of these, diethyl ether, tetrahydrofuran,N,N-dimethylformamide and dioxane are preferred.

The reaction temperature may usually range from -70° C. to the boilingpoint of the solvent used for the reaction and preferably from -20° C.to 100° C. Under these conditions, the reaction can usually be completedin a period of time ranging from 5 minutes to 7 days and preferably from10 minutes to 24 hours.

The proportion of the compound of formula [IV] or a salt thereof to thecompound of formula [III] is not critical and may vary according to thekinds of individual compounds, the reaction conditions employed andother factors. Whereas, the compound of formula [IV] or a salt thereofmay usually be used in an amount of 1 to 5 moles, preferably 1 to 2moles, per mole of the compound of formula [III].

The coupled compound of the above formula [IX] can also be obtained byconverting the carboxylic acid of formula [III] into a reactivederivative thereof and condensing it with the compound of formula [IV]or a salt thereof.

Suitable reactive derivatives of the carboxylic acid of formula [III]include, for example, compounds which are commonly used in the field oforganic synthetic chemistry for activation of carboxyl group(s) in anesterification or amidation reaction, such as mixed acid anhydrides,active esters and active amides.

Mixed acid anhydrides of the carboxylic acid of formula [III] can beobtained by reacting the carboxylic acid of formula [III] with an alkylchlorocarbonate, e.g., ethyl chlorocarbonate, an aliphatic carboxylicacid chloride, e.g., acetyl chloride, pivaloyl chloride or the likeaccording to conventional method. Reactive esters thereof can beobtained by reacting the carboxylic acid of formula [III] with anN-hydroxy compound, e.g., N-hydroxysuccinimide, N-hydroxyphthalimide or1-hydroxybenzotriazole; or a phenol compound, e.g., 4-nitrophenol,2,4-dinitrophenol, 2,4,5-trichlorophenol, pentachlorophenol or the like;in the presence of a condensing agent, e.g.,N,N'-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, diphenylphosphoryl azideor dipyridyl disulfide-triphenylphosphine, according to conventionalmethod. Reactive amides thereof can be obtained by reacting thecarboxylic acid of formula [III] with 1,1'-carbonyldiimidazole,1,1'-carbonylbis(2-methylimidazole) or the like according toconventional method.

The condensation reaction of a reactive derivative of a carboxylic acidof formula [III] with a compound of formula [IV] or a salt thereof ispreferably carried out in an inert solvent. Suitable inert organicsolvents include, for example, diethyl ether, tetrahydrofuran,N,N-dimethylformamide, dioxane, benzene, toluene, chlorobenzene,methylene chloride, chloroform, carbon tetrachloride, dichloroethane,trichloroethylene and mixtures of the foregoing solvents. Of these,diethyl ether, chloroform, tetrahydrofuran, N,N-dimethylformamide anddioxane are preferred.

The reaction temperature may usually range from -70° C. to the boilingpoint of the solvent used for the reaction and preferably from -20° C.to 100° C.

The proportion of the compound of formula [IV] or a salt thereof to thereactive derivative of a carboxylic acid of formula [III] is notcritical and may vary according to the kind of the reactive derivativeand other factors, while the compound of formula [IV] or a salt thereofmay usually be used in an amount of 1 to 5 moles, preferably 1 to 2moles, per mole of the reactive derivative of the carboxylic acid offormula [III].

In the coupled compounds expressed by the general formula [IX], when R¹⁰is a C₃ -C₆ cycloalkyl group having 1-2 unprotected or protectedhydroxyl or oxo group(s), or R²⁰ is an aliphatic hydrocarbon grouphaving 1-2 unprotected or protected hydroxyl or oxo group(s), thehydroxyl or oxo group(s) are converted to fluorine atom(s) either asthey are or after removing the protective group(s).

Removal of protective groups from hydroxyl and oxo groups which areprotected in the form of ketals in the compounds of formula [IX] cannormally be effected in aqueous solvent, using an inorganic acid, anorganic acid, a weakly acidic salt or the like. Suitable inorganic acidsinclude, for example, hydrochloric acid and sulfuric acid; suitableorganic acids include, for example, p-toluenesulfonic acid,benzenesulfonic acid, camphor-sulfonic acid and acetic acid; andsuitable weakly acidic salts include, for example, ammonium chloride andpyridinium p-toluenesulfonate. Preferred aqueous solvents includeaqueous methanol, aqueous ethanol, aqueous tetrahydrofuran, aqueousdioxane and the like. The reaction may usually be carried out in thepresence of a catalytic amount to 5 equivalents, preferably a catalyticamount to 1 equivalent, of such an acid or salt at a temperature rangingfrom 0° C. to 100° C. and preferably from room temperature to 80° C.

Conversion of the hydroxyl or oxo group(s) to fluorine atom(s) cannormally be effected by causing the compound to react in an inertsolvent which is not detrimental to the reaction, e.g., methylenechloride, chloroform, tetrahydrofuran, methanol, acetonitrile,dimethylsulfoxide or pyridine, or in the absence of a solvent, using oneequivalent to an excessive amount, preferably 1-2 equivalents, of afluorinating agent such as sulfurtetrafluoride,diethylaminosulfurtrifluoride, cesium fluorosulfate, tetrabutylammoniumfluoride, tris(dimethylamino)sulfonium-difluorotrimethylsilicate,hydrogen fluoride or tosyl fluoride, preferably at temperatures ranging-80° C.-180° C. for 10 minutes to 72 hours.

When R²⁰ in the compounds expressed by general formula [IV] or [IX] hasprotected amino group(s) or protected lower alkylamino group(s), theprotective group(s) are removed if necessary; when lower alkoxycarbonylor aryloxycarbonyl group(s) are present, the functional group(s) aresuitably converted to amino group(s). Removal of amino-protective groupscan be effected by processes known per se, for example, any of thosedescribed in Protective Groups in Organic Synthesis, T. W. Greene, JohnWiley & Sons Co. (1981) or methods analogous thereto, for example,solvolysis using an acid or base, chemical reduction using a metalhydride complex or the like and catalytic reduction usingpalladium-on-carbon, Raney-nickel or the like.

Solvolysis with an acid can normally be carried out by treating thecompound with an acid such as formic acid, trifluoroacetic acid,hydrochloric acid or sulfuric acid, in an inert solvent such asmethylene chloride, anisole, tetrahydrofuran, dioxane, methanol orethanol or a mixture of such a solvent and water, or in the absence ofsolvent, preferably at a temperature in the range from about 0° to about100° C., for a period of time ranging from 10 minutes to 24 hours.

Solvolysis with a base can normally be carried out by treating thecompound with an alkali metal hydroxide, e.g., lithium hydroxide, sodiumhydroxide or potassium hydroxide; an alkali metal carbonate, e.g.,sodium carbonate or potassium carbonate, in an inert solvent whichexerts no adverse effect on the reaction, e.g., methanol, ethanol,isopropanol, tetrahydrofuran or dioxane or a mixture of such a solventand water, preferably at a temperature in the range of from about -20 toabout 80° C., for a period of time ranging from 10 minutes to 24 hours.

Catalytic reduction can normally be carried out in the presence of acatalyst such as palladium-on-carbon, palladium hydroxide, Raney nickelor platinum oxide, in an inert solvent, e.g., methanol, ethanol, wateror acetic acid or a mixture of such solvents, preferably under apressure of hydrogen of about 1 to about 20 kg/cm², preferably at atemperature in the range of from about 0 to about 40° C., for a periodof time ranging from 10 minutes to 24 hours.

Conversion of the lower alkoxycarbonyl or aryloxycarbonyl to amino canbe conducted by either reacting the compound with hydrazine to form anacid hydrazide and thereafter converting it to the corresponding acidazide; or converting the compound to a carboxylic acid by hydrolysis,then to an acid azide, followed by rearrangement and hydrolysis.

In the process variant (b), the condensation reaction of a carboxylicacid of formula [III] or a reactive derivative thereof with a piperidinederivative of formula [V] in the first stage can be practiced in themanner similar to the condensation reaction of a carboxylic acid offormula [III] or a reactive derivative thereof with a compound offormula [IV] in the process variant (a).

The compound of the foregoing formula [VI] obtained through thiscondensation reaction is then removed of the protective group(s) ofimino group(s).

Removal of said imino-protective groups from a compound of formula [VI]can be effected in the manner similar to above-described removal ofamino-protective groups.

Thus obtained compounds of the general formula [X] ##STR8## [wherein Ar,R¹⁰ and X are as defined above] is reacted with a compound of formula[VII] in the second stage, if necessary in the presence of a base.

The reaction of the compound of formula [X] with the compound of formula[VII] is usually carried out in a suitable solvent by using thecompounds in substantially equimolar amounts or using either of thecompounds in slight excess (e.g., using the compound of formula [VII] inan amount of 1 to 1.3 moles per mole of the compound of formula [X]). Ifdesired, however, either of the compounds may be used in large excess.Moreover, a suitable base and/or an additive may be used.

Suitable solvents include, for example, ethers such as diethyl ether,tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene,toluene, chlorobenzene and xylene; aprotic polar solvents such asdimethyl sulfoxide, N,N-dimethylformamide, acetonitrile andhexamethyiphosphoric triamide; and mixtures thereof.

Bases which can be used for above-described reaction include, forexample, alkali metal bicarbonates such as sodium hydrogen carbonate andpotassium hydrogen carbonate; alkali metal carbonates such as sodiumcarbonate and potassium carbonate; tertiary aliphatic amines such astrimethylamine, triethylamine, N,N-diisopropylethylamine,N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and1,5-diazabicyclo[4.3.0]non-5-ene (DBN); and aromatic amines such aspyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline andisoquinoline. Of these, N,N-diisopropylethylamine and potassiumcarbonate are preferred.

Additives which can be used for above-described reaction include, forexample, alkali metal iodides such as lithium iodide, sodium iodide andpotassium iodide. Of these, potassium iodide is preferred.

The reaction temperature may usually range from about 0° C. to theboiling point of the solvent, and the reaction time may usually rangefrom 10 minutes to 48 hours. If desired, however, reaction conditionsbeyond these limits may be used.

If necessary, furthermore, conversion reactions of R¹⁰ and R²⁰ asdescribed as to the process variant (a) are conducted.

The reductive alkylation reaction of a compound of the above formula [X]with an aldehyde of formula [VIII] according to the process variant (c)is normally carried out in an inert solvent which exerts no adverseeffect on the reaction. Suitable inert solvents include, for example,alcohols such as methanol and ethanol; ethers such as diethyl ether,tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene andtoluene; and mixtures thereof. Of these, methanol, ethanol,tetrahydrofuran and toluene are preferred.

The reaction temperature may usually range from about -30° C. to about200° C. and preferably from about 0° C. to about 100° C. The reactiontime may usually range from 10 minutes to 7 days and preferably from 10minutes to 24 hours.

The above-described reductive alkylation reaction is preferably carriedout under weakly acidic conditions which facilitate formation of Schiffbases. Acids which can be used for the necessary pH control include, forexample, p-toluenesulfonic acid, hydrochloric acid, acetic acid andtrifluoroacetic acid.

The reductive alkylation can be effected, for example, using a metalhydride complex such as sodium borohydride, sodium cyanoborohydride,lithium aluminum hydride or sodium triacetoxyborohydride, or bycatalytic reduction using a palladium-on-carbon catalyst, a Raney nickelcatalyst or the like. Preferably, it is effected using a metal hydridecomplex such as sodium borohydride or sodium cyanoborohydride.Especially when the reductive alkylation is carried out under weaklyacidic conditions which facilitate formation of Schiff bases, it ispreferable to use sodium cyanoborohydride or the like which arerelatively stable in the acidic pH range.

When a metal hydride complex is used as the reducing agent, the amountof reducing agent used may usually range from 1 mole to excessive moles,preferably from 1 to 10 moles, per mole of the compound of formula [X].

If necessary, then the conversion reactions of R¹⁰ and R²¹ as describedas to the process variant (a) are carried out.

The compounds of formula [I] which are obtained according to theabove-described process variants (a), (b) and (c) can be isolated andpurified by those methods known per se, i.e. such customarily usedseparation means as column chromatography using silica gel, adsorbentresin or the like, liquid chromatography, thin-layer chromatography,solvent extraction or recrystallization and reprecipitation.

The compounds of the present invention and intermediates thereof existin stereoisomeric forms such as enantiomeric isomers, diastereoisomersand geometrical isomers. It is to be understood that the compounds ofthe present invention also include all such stereoisomerically puresubstances and mixtures thereof. When the compounds of the presentinvention and intermediates thereof are racemates, their opticalresolution can be achieved by conventional means such ashigh-performance liquid chromatography using a chiral carrier orfractional crystallization of a diastereomeric salt.

The compounds of formula [I] obtained in the above-described manner maybe converted into pharmaceutically acceptable salts thereof according tousual manner. Conversely, such salts may also be converted into thecorresponding free amines according to usual manner.

The compounds of formula [I] in accordance with the present inventionexhibit potent and selective inhibitory activity for binding tomuscarinic receptors, a potent and selective antagonism to muscarinicreceptors in vitro and, furthermore, potent and durable bronchodilatoryaction in vivo. These activities exhibited by the compounds of thepresent invention are demonstrated by the following tests on theinhibition of binding to muscarinic receptors and tests on antagonismagainst various muscarinic receptors.

Tests on inhibition of binding to muscarinic receptors

These tests were performed according to a modification of the method ofHargreaves et al. (Br. J. Pharmacol. 107: 494-501, 1992). Membranes fromCHO cells expressing cloned human m1-m5 (Receptor Biology, Inc.) wereincubated with 0.2 nM [³ H]-N-methylscopolamine and each a compound ofthe present invention to be tested in 0.5 ml of 50 mM Tris-HCl--10 mMMgCl₂ --1 mM EDTA (pH 7.4) for 2 hours at 25° C. Free and membrane-bound[³ H]-N-methylscopolamine were separated by filtration over glassfilters (UniFilter-GF/C; Packard Instruments Co., Inc.) using cellharvester (Filtermate™ 196; Packard Instruments Co., Inc.). Then thefilter was washed four times with 1 ml of ice-cold Tris-HCl (pH 7.4) anddried at 50° C. After adding a scintillator (Microscinti 0; PackardInstruments Co., Inc.), the radioactivity was counted by a liquidscintillation counter (TopCount™; Packard Instruments Co., Inc.).Non-specific binding was measured in the presence of 1 μMN-methylscopolamine. According to the method of Cheng and Prussoff(Biochem. Pharmacol. 22: 3099-3108, 1973), the binding affinity (Kivalue) of the test compound (i.e., a compound of the present invention)for muscarinic receptors was calculated from the concentration of thetest compound which achieved 50% inhibition of binding of [³H]-N-methylscopolamine (IC₅₀ value).

                  TABLE 1                                                         ______________________________________                                        Inhibitory Effects on Binding to                                              Muscarinic M.sub.2 and M.sub.3 Receptors                                                     Ki (nM)                                                                      M.sub.2  M.sub.3                                                                              M.sub.2 /M.sub.3                                ______________________________________                                        Compound of Example 1                                                                          3200      5.5    590                                         Compound of Example 10                                                                        17000      8.9    1900                                        Compound of Example 11                                                                         460       3.2    140                                         Compound of Example 12                                                                         8600      30     290                                         Compound of Example 14                                                                         1400      10     140                                         Compound of Example 15                                                                         1000      3.5    290                                         Compound of Example 20                                                                         550       3.0    180                                         Compound of Example 21                                                                        50000      22     2300                                        Compound of Example 22                                                                        13000      19     680                                         Compound of Example 26                                                                        24000      22     1100                                        Compound of Example 27                                                                         4200      20     210                                         Compound of Example 31                                                                        10000      19     520                                         ______________________________________                                    

As is clear from the results indicated in above Table 1, those compoundsof the present invention exhibited far higher binding-inhibitoryactivity to M₃ receptor, than to M₂ receptor.

Tests for Antagonism to Muscarinic Receptors (in vitro)

1) Tests for antagonism to M₂ receptor in an isolated rat right atrium

These tests were performed according to a conventional method. A male SDstrain rat (weighing 300-500 g) was killed by exsanguination, and theright atrium was isolated. This preparation was isometrically suspendedin organ bath filled with 20 ml of Krebs-Henseleit solution (gassed with95% O₂ --5% CO₂ and kept at 32° C.) with an initial tension of 0.5 g.The heart rate was recorded with a heart rate counter. After thepreparation was equilibrated for 30 minutes, carbachol (10⁻⁹ to 10⁻⁶ M)was cumulatively administered in three-fold increasing doses. Thus, adecrease in heart rate was measured to obtain a dose-response curve forthe control experiment. After the preparation was washed with freshsolution to restore the heart rate, a test compound was administeredthereto. Ten minutes later, carbachol was cumulatively administeredagain. Responses to carbachol were expressed as percentages based on theheart rate before administration of carbachol as 100%. The antagonisticpotency (K_(B) value) of the test compound was determined from thedegree of shift of the dose-response curve obtained by treatment withindividual test compound of the present invention.

2) Tests for antagonism to the airway M₃ receptor in an isolated rattrachea

These tests were performed according to a conventional method. A male SDstrain rat (weighing 300-500 g) was killed by exsanguination, and thetrachea was isolated. Annular segments (2 mm wide) were cut out from thetrachea and cut transversely at the anterior cartilage part to make openring preparation. A preparation was suspended in a Magnus tube filledwith 5 ml of Krebs-Henseleit solution (gassed with 95% O₂ --5% CO₂ andkept at 32° C.) with an initial tension of 1.0 g and a resting tensionof 0.6 g. The tension of the preparation was recorded isometrically.After being equilibrated for an hour, the preparation was made tocontract twice by treatment with 10⁻⁴ M carbachol, and the secondcontraction induced by carbachol was used as the reference contraction.After the preparation was washed with fresh solution to be restored tothe base line, a test compound was administered thereto (or no treatmentwas given). Ten minutes later, carbachol (10⁻⁸ to 10⁻³ M) wascumulatively administered in three-fold increasing doses to obtain adose-response curve. The dose-response curve was plotted by expressingresponses as percentages based on the reference contraction of thepreparation as 100%. The antagonistic potency (K_(B) value) of the testcompound was determined from the degree of shift of the dose-responsecurve obtained by treatment with the test compound.

                  TABLE 2                                                         ______________________________________                                        Antagonism to Muscarinic Receptors (in vitro)                                               K.sub.B (nM)                                                                  right atrium                                                                           Trachea                                                              M.sub.2  M.sub.3 M.sub.2 /M.sub.3                               ______________________________________                                        Compound of Example 1                                                                         1000       6.3     160                                        Compound of Example 11                                                                         610       0.95    640                                        Compound of Example 20                                                                        2100       1.6     630                                        ______________________________________                                    

As is clear from the results indicated in above Table 2, the compoundsof the present invention exhibited far more powerful antagonism to thetrachea M₃ receptor than to the right atrium M₂ receptor. Therefore, thecompounds of the present invention are more selective for trachea M₃receptor.

Tests for antagonism against muscarinic M₃ receptor (in vivo)

1-A) Tests for bronchodilation in rats (i.v.)

Eight- to eleven-weeks-old male rats of the Sprague-Dawley strain,weighing 380-420 g, were anesthetized with urethane (750 mg/kg. i.p.)and α-chloralose (37.5 mg/kg, i.p.). The bronchus of each rat wasintubated, and the right jugular vein was cannulated for drugadministration. After spontaneous respiration was fully suppressed bysuccinylcholine (5 mg/kg, s.c.), the airway resistance was measuredunder artificial ventilation by means of a Pulmonary Mechanics Model 6(Buxco). To evoke an increase in airway resistance, acetylcholine (50μg/kg, i.v.) was administered to the animals. The acetylcholine-inducedairway resistance increase was measured 5 minutes before and 5 minutesafter administration of test compound, and the ratio of the airwayresistance of the latter to the former was calculated. In controls,isotonic sodium chloride solution was used in place of the testcompounds and otherwise identical procedures were repeated, thecalculated ratio being set to be 100%. A dose that inhibited theacetylcholine-induced increase in airway resistance in the controlgroups by 50% was defined to be ED₅₀, and the ED₅₀ values of the testcompounds were calculated by probit analysis of their dose-responsecurves.

1-B) Tests for bronchodilation in rats (p.o.)

Eight- to eleven-weeks-old male rats of Sprague-Dawley strain weighing380-420 g were orally administered with a test compound. The rats weretreated in the identical manner as in the i.v. test, starting 30 minutesafter the administration, and their airway resistance values weremeasured. The acetylcholine-(50 μg/kg, i.v.) induced airway resistanceincrease were measured 60 minutes after the administration of testcompounds. In controls, isotonic sodium chloride solution was used inplace of the test compounds and otherwise identical procedures wererepeated, the ratio between the two airway resistance values wherebybeing set to be 100%. A dose that inhibited the acetylcholine-inducedincrease in airway resistance in the control groups by 50% was definedto be ED₅₀, and the ED₅₀ values of the test compounds were calculated byprobit analysis of their dose-response curves.

                  TABLE 3                                                         ______________________________________                                        Antagonism to Muscarinic Receptor (in vivo)                                                     Inhibition of Airway                                                          Contraction                                                                   ED.sub.50 (mg/kg)                                                             iv    po                                                    ______________________________________                                        Compound of Example 1                                                                             0.033   --                                                Compound of Example 11                                                                            0.032   0.22                                              Compound of Example 20                                                                            0.040   0.37                                              Compound of Example 26                                                                            0.37    0.95                                              atoropine           0.0043  --                                                ipratropium         0.0015  --                                                ______________________________________                                    

2) Tests for bronchodilation in dogs (p.o.)

Twelve- to twenty-four-months-old male beagle dogs (weighing 10-15 kg)were anesthetized with pentobarbital (30 mg/kg, i.v.) and intubated intheir bronchus. Their airway sensitivity to inhaled methacholine weremeasured at least twice at two-weeks interval, and the dogs showing areproducible methacholine reaction threshold values¹) ware selected. Tothose dogs whose methacholine reaction threshold value had beenconfirmed, the test compounds were orally administered (1 mg/kg). Fourhours after the administration, the methacholine provocation test wasconducted, and then the methacholine reaction threshold value²) afteradministration of the test compound was obtained.

The bronchodilator activity of the test compound was determinedfollowing equation: ##EQU1##

The methacholine provocation test was conducted using AstographTCK-6100H Model (Chest). Methacholine chloride was used asbronchoconstritor, which was diluted with isotonic sodium chloridesolution in 10-grade concentration levels starting from 40,000 μg/ml, as20,000, 10,000, 5,000, 2,500, 1,250, 625, 312.5, 156 and 78 μg/ml. Thesemethacholine aerosols were inhaled to the test animal each for 1 min,starting from the lowest concentration level, and respiration resistancewas continuously recorded. The concentration level at which therespiration resistance reached twice the initial value was recorded asthe methacholine threshold value.

                  TABLE 4                                                         ______________________________________                                        Bronchodilation Activity in Dogs                                              (Oral Administration)                                                                       Methacholine Inhalation-inducing                                              Test (1 mg/kg, p. o.)                                                         shift value (after 4 hrs.)                                      ______________________________________                                        Compound of Example 11                                                                         21                                                           Compound of Example 20                                                                        >69                                                           Compound of Example 26                                                                        >64                                                           ______________________________________                                    

As clearly demonstrated in above Table 4, the compounds of the presentinvention exhibited powerful bronchodilation action and long duration ofthe action.

As above, the compounds of formula [I] of the present invention, whichare characterized by introduction of fluorine atom(s) thereinto, exhibitpotent and selective antagonistic activity against muscarinic M₃receptors and exhibit excellent oral activity, duration of action andpharmacokinetics. Hence, they can be administered to patients orally orparenterally as safe pharmaceutics exhibiting little side effects, inthe treatment or prophylaxis of diseases such respiratory diseases aschronic obstructive pulmonary diseases, chronic bronchitis, asthma andrhinitis: digestive diseases such as irritable bowel syndrome,convulsive colitis, diverticulitis and pain accompanying contraction ofsmooth muscles of the digestive system: urinary disorders like urinaryincontinence and frequency in neurogenic pollakiurea, neurogenicbladder, nocturnal enuresis, unstable bladder; cystospasm and chroniccystisis: and motion sickness.

In practically using the compounds of the present invention for thetreatment or prophylaxis of such diseases, they may be combined withpharmaceutically acceptable adjuvants in the usual manner to preparepharmaceutical compositions suitable for administration. For thispurpose, there can be used a variety of adjuvants which are commonlyused in the field of pharmaceutics. Such adjuvants include, for example,gelatin, lactose, sucrose, titanium oxide, starch, crystallinecellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, cornstarch, microcrystalline wax, white petrolatum, magnesium aluminatemetasilicate, anhydrous calcium phosphate, citric acid, trisodiumcitrate, hydroxypropyl cellulose, sorbitol, sorbitan fatty acid ester,polysorbate, sucrose fatty acid ester, polyoxyethylene, hardened castoroil, polyvinyl pyrrolidone, magnesium stearate, light anhydrous silicicacid, talc, vegetable oil, benzyl alcohol, acacia, propylene glycol,polyalkylene glycol, cyclodextrin and hydroxypropylcyclodextrin.

The dosage forms of pharmaceutical compositions prepared by using theseadjuvants include solid preparations such as tablets, capsules,granules, powders and suppositories; liquid preparations such as syrups,elixirs and injections; and the like. These preparations may beformulated according to conventional techniques well-known in the fieldof pharmaceutics. Liquid preparations may be in a form which isdissolved or suspended in water or other suitable medium prior to use.In particular, injections may be in the form of a solution or suspensionin physiological saline solution or a glucose solution, or in powderform for reconstitution by dissolution or suspension in physiologicalsaline or a glucose solution prior to use. If desired, such injectionsmay contain buffer agents and/or preservatives.

As preparations for oral administration, such formulation forms, besidesordinary tablets, capsules, granules, powders and the like, aerosols ordry powders for inhalation, elixirs containing spices or coloring agentsor suspensions may be employed.

In these pharmaceutical compositions, a compound in accordance with thepresent invention may be present at a ratio of from 1.0 to 100% byweight, preferably 1.0 to 60% by weight, based on the total weight ofthe composition. These pharmaceutical compositions may additionallycontain other therapeutically effective compounds.

When the compounds of the present invention are used as drugs, theirdosage level and dosage schedule may vary according to the sex, age andbody weight of the patient, the severity of symptoms, the type and rangeof the desired therapeutic effect, and the like. Generally for oraladministration, they are preferably administered in a daily dose of 0.1to 100 mg/kg for adults and this daily dose may be given at a time or inseveral divided doses. For parenteral administration, they arepreferably administered in a daily dose of 0.001 to 10 mg/kg for adultsand this daily dose may be given at a time or in several divided doses.

Hereinafter the present invention is more specifically explained withreference to working examples, it being understood that the examples arein no way limitative of the scope of the invention.

EXAMPLE 1

(2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR9## Step 1. Synthesis of1-(4-methyl-3-pentenyl)-4-piperidone

To a solution of 2.5 g of 4-piperidone monohydrochloride monohydrate in150 ml of acetonitrile, 11 g of potassium carbonate, 2.62 g of5-bromo-2-methyl-2-pentene and 800 mg of potassium iodide were addedsequentially, and the mixture was heated under reflux for 3 hours. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with brine, and dried over anhydrous magnesium sulfate. Distillingthe solvent off under reduced pressure, 2.24 g of the title compound wasobtained as a white solid.

Step 2. Synthesis of 4-amino-1-(4-methyl-3-pentenyl)piperidine

To a solution of 2.2 g of 1-(4-methyl-3-pentenyl)-4-piperidone in 60 mlof methanol, 1.1 g of ammonium acetate and 860 mg of sodiumcyanoborohydride were added sequentially, at room temperature, followedby stirring overnight at same temperature. Distilling the methanol offunder reduced pressure, the pH of the reaction media was adjusted to 3with 1N hydrochloric acid, followed by washing with diethyl ether. Theaqueous layer was basified with 1N aqueous sodium hydroxide solution andextracted with chloroform. The organic layer was washed with water andthen brine, and dried over anhydrous magnesium sulfate. Distilling thesolvent off under reduced pressure, 1.9 g of the title compound wasobtained as a colorless oil.

Step 3. Synthesis of(2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

To a solution of 75 mg of(2R)-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid in 3ml of N,N-dimethylformamide, 55 mg of 1,1'-carbonyldiimidazole was addedat room temperature, followed by stirring for 2 hours at the sametemperature. Then 60 mg of 4-amino-1-(4-methyl-3-pentenyl)piperidine and5 mg of 4-dimethylaminopyridine were added sequentially, followed bystirring overnight at room temperature. The reaction mixture was dilutedwith diethyl ether, washed with saturated aqueous sodium bicarbonatesolution, water and brine, and dried over anhydrous magnesium sulfate.Distilling the solvent off under reduced pressure, the resulting residuewas purified by preparative thin layer chromatography [Kieselgel™60F₂₅₄, Art 5744 (manufactured by E. Merck); chloroform/methanol=10/1],to provide 23 mg of the title compound as an oil.

¹ H-NMR (CDCl₃, δ ppm): 1.32-1.50 (2H, m), 1.60 (3H, s), 1.68 (3H, s)1.58-2.34 (12H, m), 2.43-2.49 (1H, m) 2.73-2.82 (3H, m), 3.23-3.36 (1H,m), 3.48 (1H, brs), 3.62-3.73 (1H, m), 5.03-5.08 (1H, m), 6.29-6.33 (1H,m), 7.25-7.39 (3H, m), 7.54-7.57 (2H, m)

low resolution FAB-MS (m/e, (C₂₄ H₃₄ F₂ N₂ O₂ +H)⁺): 421.

EXAMPLE 2

(2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR10##

The title compound was prepared in the same manner as described in step3 of Example 1 using(2R)-[(1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid.

¹ H-NMR (CDCl₃, δ ppm): 1.60 (3H, s), 1.68 (3H, s), 1.35-2.48 (15H, m),2.75-2.86 (3H, m), 3.22-3.36 (1H, m), 3.48 (1H, brs), 3.61-3.76 (1H, m),5.03-5.08 (1H, m), 6.27 (1H, d, J=8.0 Hz), 7.26-7.40 (3H, m), 7.55-7.58(2H, m)

low resolution FAB-MS (m/e, (C₂₄ H₃₄ F₂ N₂ O₂ +H)⁺): 421.

EXAMPLE 3

(2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1S,3S)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamideand(2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1S,3R)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formulae ##STR11##

The title compounds were prepared using(2R)-[(1S)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetic acid, in thesame manner as described in step 3 in Example 1, and separated in thefinal step.

(2R)-N-[1-(4-methyl-3-pentenyl)-piperidin-4-yl]-2-[(1S,3S)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide

¹ H-NMR (CDCl₃, δ ppm): 1.60 (3H, s), 1.68 (3H, s), 1.31-2.33 (15H, m),2.44-2.49 (1H, m), 2.69-2.81 (2H, m), 3.19-3.30 (1H, m), 3.62-3.74 (1H,m), 3.90 (1H, brs), 5.03-5.28 (2H, m), 5.87-5.91 (1H, m), 7.25-7.40 (3H,m), 7.53-7.57 (2H, m)

low resolution FAB-MS (m/e. (C₂₄ H₃₅ FN₂ O₂ +H)⁺): 403

(2R)-N-[1-(4-methyl-3-pentenyl)-piperidin-4-yl]-2-[(1S,3R)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide

¹ H-NMR (CDCl₃, δ ppm): 1.61 (3H, s) 1.68 (3H, s), 1.37-2.26 (14H, m),2.32-2.37 (2H, m), 2.75-2.90 (2H, m), 3.43-3.56 (1H, m), 3.62-3.76 (1H,m), 5.04-5.13 (2H, m), 6.91-6.95 (1H, m), 7.23-7.35 (3H, m) 7.67-7.71(2H, m)

low resolution FAB-MS (m/e, (C₂₄ H₃₅ FN₂ O₂ +H)⁺): 403.

EXAMPLE 4

(2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1R,3S)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamideand(2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1R,3R)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formulae ##STR12##

The title compounds were prepared using(2R)-[(1R)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetic acid, in thesame manner as described in step 3 in Example 1, and separated in thefinal step.

(2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1R,3S)-3-fluorocyolopentyl]-2-hydroxy-2-phenylacetamide

¹ H-NMR (CDCl₃, δ ppm): 1.60 (3H, s) 1.70 (3H, s), 1.38-2.17 (14H, m),2.27-2.32 (2H, m), 2.70-2.81 (2H, m), 3.19-3.32 (1H, m), 3.63-3.74 (1H,m), 3.93 (1H, brs), 5.00-5.21 (2H, m), 5.96-6.02 (1H, m), 7.26-7.38 (3H,m), 7.55-7.58 (2H, m)

low resolution FAB-MS (m/e, (C₂₄ H₃₅ FN₂ O₂ +H)⁺): 403

(2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-[(1R,3R)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide

¹ H-NMR (CDCl₃, δ ppm) 1.60 (3H, s), 1.68 (3H, s), 1.38-2.32 (6H, m)2.74-2.88 (2H, m), 3.41-3.52 (1H, m), 3.63-3.74 (1H, m), 5.02-5.21 (2H,m), 6.90 (1H, d, J=8.2 Hz), 7.23-7.35 (3H, m), 7.66-7.69 (2H, m)

low resolution FAB-MS (m/e, (C₂₄ H₃₅ FN₂ O₂ +H)⁺) 403.

EXAMPLE 5

N-[1-[(3Z)-4-trifluoromethyl-3-pentenyl]piperidin-4-yl]-2-cycolopentyl-2-hydroxy-2-phenylacetamide

Structural formula ##STR13## Step 1. Synthesis ofN-(piperidin-4-yl)-2-cyclopentyl-2-hydroxy-2-phenylacetamide

To a solution of 3.51 g of 2-cyclopentyl-2-hydroxy-2-phenylacetic acidin 40 ml of N,N-dimethylformamide, 2.63 g of 1,1'-carbonyldiimidazolewas added and stirred at room temperature for 2 hours. To the reactionmixture 3.96 g of 4-amino-1-(t-butoxycarbonyl)piperidinemonohydrochloride, 200 mg of 4-dimethylaminopyridine and 6.9 ml ofdiisopropylethylamine were added, followed by stirring overnight at roomtemperature. Saturated aqueous sodium bicarbonate solution was added tothe reaction mixture followed by an extraction with diethyl ether. Theorganic layer was washed with brine and dried over anhydrous sodiumsulfate. Distilling the solvent off under reduced pressure, theresultant residue was purified by silica gel column chromatography(developing solvent: hexane/ethyl acetate=3/1) to provide 2.84 g of awhite solid. The solid was dissolved in 30 ml of 10% hydrochloricacid-methanol, and stirred overnight at room temperature. Distilling themethanol off under reduced pressure, the residue was diluted with waterand washed with diethyl ether. The aqueous layer was made basic withsodium hydroxide and extracted with chloroform. The organic layer waswashed with water and then with brine, and dried over anhydrousmagnesium sulfate. Distilling the solvent off under reduced pressure,2.15 g of the title compound was obtained as a white solid.

Step 2. Synthesis of (3Z)-4-trifluoromethyl-3-pentenylt-butyldiphenylsilyl ether

To a solution of 2.94 g of (3-t-butyldiphenylsilyloxypropyl)triphenylphosphoniumbromide in 40 ml of tetrahydrofuran, 2.5ml of 1.7 M hexane solution of n-butyllithium was added dropwise at -78°C. The temperature was raised to -20° C. After stirring for an hour atsaid temperature, reaction mixture was cooled to -78° C. into which 0.5ml of trifluoroacetone was added dropwise, followed by stirringovernight while raising the temperature to room temperature. Thereaction liquid was diluted with hexane, washed with 10% hydrochloricacid, water and then brine, and dried over anhydrous magnesium sulfate.Distilling the solvent off under reduced pressure, resulting residue waspurified by silica gel column chromatography (developing solvent:hexane/ethyl acetate=9/1) to provide 1.44 g of the title compound.

Step 3. Synthesis of (3Z)-4-trifluoromethyl-3-pentenol

To a solution of 1.44 g of (3Z)-4-trifluoromethyl-3-pentenylt-butyl-diphenylsilyl ether in 8 ml of tetrahydrofuran, 4.4 ml of 1.0 Msolution of tetrabutylammonium fluoride in tetrahydrofuran was added,followed by stirring for 2 hours at room temperature. The reactionmixture was diluted with diethyl ether, washed with water and thenbrine, and dried over anhydrous magnesium sulfate. Distilling thesolvent off under reduced pressure, the residue was purified by silicagel column chromatography (developing solvent: ethyl acetate) to provide414 mg of the title compound.

Step 4. Synthesis of (3Z)-4-trifluoromethyl-3-pentenylp-toluenesulfonate

To a solution of 414 mg of (3Z)-4-trifluoromethyl-3-pentenol in 6 ml ofpyridine, 565 mg of p-toluenesulfonyl chloride was added under coolingwith ice, followed by stirring for 16 hours at room temperature. Thereaction mixture was diluted with diethyl ether, washed with water andthen brine, and dried over anhydrous magnesium sulfate. Distilling thesolvent off under reduced pressure, the residue was purified by silicagel column chromatography (developing solvent: hexane/ethyl acetate=9/1)to provide 412 mg of the title compound.

Step 5. Synthesis ofN-[1-[(3Z)-4-trifluoromethyl-3-pentenyl]piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide

To a solution of 77 mg ofN-(piperidin-4-yl)-2-cyclopentyl-2-hydroxy-2-phenylacetamide in 3 ml ofN,N-dimethylformamide, 74 mg of (3Z)-4-trifluoromethyl-3-pentenylp-toluenesulfonate, 102 mg of potassium carbonate and 43 mg of potassiumiodide were added by the order stated, followed by 3 hours' heatingunder reflux. The reaction liquid was diluted with diethyl ether, washedwith water and saturated saline solution by the order stated, and driedover anhydrous magnesium sulfate. Distilling the solvent off underreduced pressure, the residue was purified by preparative thin layerchromatography (Kieselgel™ 60F₂₅₄, Art 5744 (Merck)chloroform/methanol=9/1) to provide 27 mg of the title compound as anoily substance.

¹ H-NMR (CDCl₃, δ ppm): 1.12-1.88 (16H, m), 1.83 (3H, s), 2.01-2.13 (2H,m), 2.68-2.80 (2H, m), 2.97-3.10 (1H, m), 3.13 (1H, brs), 3.62-3.76 (1H,m), 5.65-5.72 (1H, m), 6.32 (1H, d, J=8.5 Hz), 7.23-7.36 (3H, m), 7.59(2H, d, J=7.3 Hz)

low resolution FAB-MS (m/e, (C₂₄ H₃₃ F₃ N₂ O₂ +H)⁺): 439.

EXAMPLE 6

N-[1-[(3Z)-4-fluoromethyl-3-pentenyl]piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide

Structural formula ##STR14##

The title compound was prepared by the procedures similar to steps 2-5of Example 5, using fluoroacetone.

¹ H-NMR (CDCl₃, δ ppm): 1.04-2.16 (14H, m), 1.79 (3H, s), 2.16-2.28 (2H,m), 2.28-2.40 (2H, m), 2.66-2.86 (2H, m) 2.94-3.24 (2H, m), 3.62-3.78(1H, m), 4.86 (2H, d, J=47.5 Hz), 5.34-5.44 (1H, m), 6.36 (1H, d, J=8.3Hz), 7.22-7.40 (3H, m), 7.56-7.64 (2H, m)

EXAMPLE 7

N-[1-[(3E)-4-fluoromethyl-3-pentenyl]piperidin-4-yl]-2-cyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR15## Step 1. Synthesis of(2E)-5-bromo-2-methyl-2-pentenol

To a solution of 681 mg of selenium dioxide in 10 ml of dichloromethane,2.5 ml of t-butyl peroxide was added at room temperature, stirred for 30minutes at said temperature, and further 2.0 g of5-bromo-2-methyl-2-pentene was added, followed by stirring for 2 hours.The reaction mixture was diluted with diethyl ether, washed with aqueoussodium thiosulfate solution, 10% aqueous potassium hydroxide solution,and then with brine, and dried over anhydrous magnesium sulfate.Distilling the solvent off under reduced pressure, the residue waspurified by silica gel column chromatography (developing solvent:hexane/ethyl acetate=20/1-4/1) to provide 1.24 g of the title compound.

Step 2. Synthesis of (2E)-5-bromo-2-methyl-2-pentenylt-butyldimethylsilyl ether

To a solution of 300 mg of (2E)-5-bromo-2-methyl-2-pentenol in 10 ml ofN,N-dimethylformamide, 302 mg of t-butyldimethylsilyl chloride and 137mg of imidazole were added, followed by stirring for an hour at roomtemperature. The reaction liquid was diluted with diethyl ether, washedwith water and then with brine, and dried over anhydrous magnesiumsulfate. Distilling the solvent off under reduced pressure. 604 mg ofthe title compound was obtained.

Step 3. Synthesis ofN-[1-[(3E)-4-t-butyldimethylsilyloxymethyl-3-pentenyl]piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide

The title compound was prepared by the method similar to step 5 ofExample 5, using (2E)-5-bromo-2-methyl-2-pentenyl t-butyldimethylsilylether.

Step 4. Synthesis ofN-[1-[(3E)-4-fluoromethyl-3-pentenyl]piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide

To a solution of 59 mg of tetrabutylammonium-fluoride trihydrate in 3 mlof tetrahydrofuran, 200 mg of molecular sieves 4A, 31 mg ofN-[1-[(3E)-4-t-butyldimethylsilyloxymethyl-3-pentenyl]piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamideand 22 mg of p-toluenesulfonylfluoride were added sequentially, followedby overnight heating under reflux at 80° C. After removal of theinsoluble material by filtration, the solvent was distilled off underreduced pressure. The remaining residue was purified by preparative thinlayer chromatography [Kieselgel™ 60F₂₅₄, Art 5744 (Merck);chloroform/methanol=20/1], to provide 11 mg of the title compound as anoily substance.

¹ H-NMR (CDCl₃ δ ppm): 1.10-1.76 (10H, m), 1.70 (3H, s), 1.76-1.95 (2H,m), 1.95-2.42 (6H, m), 2.72-2.88 (2H, m), 2.94-3.24 (2H, m), 3.62-3.78(1H, m), 4.69 (2H, d, J=47.8 Hz), 5.44-5.54 (1H, m) 6.37 (1H, d, J=8.0Hz), 7.22-7.40 (3H, m), 7.56-7.64 (2H, m)

low resolution FAB-MS (m/e, (C₂₄ H₃₅ FN₂ O₂ +H)⁺): 403

EXAMPLE 8

(2R)-N-(1-cycloheptylmethylpiperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR16##

The title compound was prepared by a method similar to the steps 1 and 5of Example 5, using(2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid andcycloheptylmethyl methanesulfonate.

¹ H-NMR (CDCl₃, δ ppm): 1.03-2.27 (27H, m), 2.63-2.71 (2H, m), 3.21-3.33(1H, m), 3.49 (1H, brs), 3.61-3.72 (1H, m), 6.23 (1H, d, J=8.3 Hz),7.27-7.39 (3H, m), 7.53-7.57 (2H, m)

low resolution FAB-MS (m/e, (C₂₆ H₃₈ F₂ N₂ O₂ +H)⁺): 449.

EXAMPLE 9

(2R)-N-[1-[(3E)-4-fluoromethyl-3-pentenyl]-piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR17##

The title compound was prepared by a method similar to Example 7, using(2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid.

¹ H-NMR (CDCl₃, δ ppm): 1.34-1.52 (2H, m), 1.69 (3H, s), 1.75-2.31 (12H,m), 2.31-2.46 (2H, m), 2.72-2.86 (2H, m), 3.24-3.38 (1H, m), 3.43 (1H,brs), 3.62-3.78 (1H, m), 4.69 (2H, d, J=47.8 Hz), 5.42-5.52 (1H, m),6.34 (1H, d, J=7.9 Hz), 7.24-7.42 (3H, m), 7.52-7.60 (2H, m)

low resolution FAB-MS (m/e, (C₂₄ H₃₃ F₃ N₂ O₂ +H)⁺): 439.

EXAMPLE 10

(2R)-N-[1-(6-methylpyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR18## Step 1. Synthesis of(2R)-N-(piperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

The title compound was prepared by a method similar to the step 1 ofExample 5, using(2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid.

Step 2. Synthesis of(2R)-N-[1-(6-methylpyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

To a solution of 17 mg of(2R)-N-(piperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamidein 2 ml of tetrahydrofuran, 3 μl of acetic acid, 12 mg of6-methylpyridine-2-carbaldehyde and 21 mg of sodiumtriacetoxyborohydride were added sequentially at room temperature, andstirred overnight at the same temperature. The reaction mixture wasdiluted with ethyl acetate, washed with brine and dried over anhydrousmagnesium sulfate. Distilling the solvent off under reduced pressure,the residue was purified by preparative thin layer chromatography(Kieselgel™ 60F₂₅₄, Art 5744 (Merck) chloroform/methanol=10/1) toprovide 9 mg of the title compound as a solid substance.

¹ H-NMR (CDCl₃, δ ppm): 1.35-1.50 (2H, m), 1.72-2.23 (10H, m), 2.53 (3H,s), 2.70-2.80 (2H, m), 3.21-3.35 (1H, m), 3.59 (2H, s), 3.60-3.78 (1H,m), 6.31 (1H, d, J=8.5 Hz), 7.02 (1H, t J=7.6 Hz) 7.18 (1H, d, J=7.6Hz), 7.28-7.39 (3H, m), 7.50 (1H, d, J=7.6 Hz), 7.53-7.59 (2H, m)

EXAMPLE 11

(2R)-N-[1-(3-thienylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR19##

The title compound was prepared by a method similar to the step 2 ofExample 10 using thiophene-3-aldehyde.

¹ H-NMR (CDCl₃, δ ppm): 1.30-1.50 (2H, m), 1.56-2.30 (10H, m), 2.66-2.82(2H, m), 3.22-3.37 (1H, m), 3.40 (1H, s), 3.49 (2H, s), 3.61-3.78 (1H,m), 6.25 (1H, d, J=8.2 Hz), 7.02 (1H, dd, J=1.1 Hz, 7.6 Hz), 7.06-7.12(1H, m), 7.22-7.42 (4H, m), 7.50-7.60 (2H, m)

low resolution FAB-MS (m/e, (C₂₃ H₂₈ F₂ N₂ O₂ S+H)⁺): 435.

EXAMPLE 12

(2R)-N-[1-(3-furylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR20##

The title compound was prepared by a method similar to the step 2 ofExample 10, using furan-3-aldehyde.

¹ H-NMR (CDCl₃, δ ppm): 1.32-1.47 (2H, m), 1.73-2.27 (10H, m), 2.70-2.78(2H, m), 3.24-3.35 (1H, m), 3.33 (2H, s), 3.42 (1H, s), 3.62-3.75 (1H,m), 6.26 (1H, d, J=7.2 Hz), 6.34 (1H, s), 7.27-7.40 (5H, m), 7.52-7.57(2H, m)

low resolution FAB-MS (m/e. (C₂₃ H₂₈ F₂ N₂ O₃ +H)⁺) 419.

EXAMPLE 13

(2R)-N-[1-(2-furylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR21##

The title compound was prepared by a method similar to the step 2 ofExample 10, using furan-2-aldehyde.

¹ H-NMR (CDCl₃, δ ppm) 1.35-1.49 (2H, m), 1.73-2.25 (10H, m), 2.70-2.80(2H, m), 3.23-3.35 (1H, m), 3.48 (1H, s), 3.49 (2H, s), 3.61-3.73 (1H,m), 6.17 (1H, d, J=3.0 Hz), 6.27-6.31 (2H, m), 7.27-7.38 (4H, m),7.52-7.56 (2H, m)

low resolution FAB-MS (m/e, (C₂₃ H₂₈ F₂ N₂ O₃ +H)⁺): 419.

EXAMPLE 14

(2R)-N-[1-(2-pyridylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR22##

The title compound was prepared by a method similar to the step 2 ofExample 10, using pyridine-2-aldehyde.

¹ H-NMR (CDCl₃, δ ppm) 1.39-1.52 (2H, m), 1.75-2.25 (10H, m), 2.70-2.80(2H, m), 3.24-3.36 (1H, m), 3.58 (1H, s), 3.61 (2H, s), 3.67-3.77 (1H,m), 6.32 (1H, d, J=7.8 Hz), 7.15 (1H, ddd, J=1.2 Hz, 4.8 Hz, 7.6 Hz),7.27-7.39 (4H, m), 7.53-7.57 (2H, m), 7.63 (1H, td, J=1.8 Hz, 7.6 Hz),8.52 (1H, ddd, J=1.2 Hz, 1.8 Hz, 3.0 Hz)

low resolution FAB-MS (m/e, (C₂₄ H₂₉ F₂ N₃ O₂ +H)⁺) 430.

EXAMPLE 15

(2R)-N-[1-(3-methoxybenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR23##

To a solution of 71 mg of(2R)-N-(piperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamidein 2 ml of N,N-dimethylformamide, 74 mg of 3-methoxybenzyl chloride and80 mg of potassium carbonate were added at room temperature, followed bystirring for about 12 hours. The reaction mixture was diluted withdiethyl ether, washed with water and then brine, and dried overanhydrous magnesium sulfate. Distilling the solvent off under reducedpressure, the residue was purified by preparative thin layerchromatography (Kieselgel™ 60F₂₅₄, Art 5744 (Merck)chloroform/methanol=9/1) to provide 75 mg of the title compound as awhite solid.

¹ H-NMR (CDCl₃, δ ppm): 1.32-1.54 (2H, m), 1.65-2.30 (10H, m), 2.68-2.85(2H, m), 3.21-3.39 (1H, m), 3.42 (1H, s) 3.45 (2H, s), 3.62-3.78 (1H,m), 3.80 (3H, s), 6.27 (1H, d, J=8.2 Hz), 6.76-6.83 (1H, m), 6.84-6.90(2H, m), 7.21 (1H, t, J=8.0 Hz), 7.24-7.40 (3H, m), 7.51-7.59 (2H, m)

low resolution FAB-MS (m/e, (C₂₆ H₃₂ F₂ N₂ O₃ +H)⁺): 459.

EXAMPLE 16

(2R)-N-(1-benzylpiperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR24##

The title compound was prepared in the same manner as described inExample 15 using benzyl bromide.

¹ H-NMR (CDCl₃, δ ppm): 1.35-1.52 (2H, m), 1.70-2.23 (10H, m), 2.70-2.81(2H, m), 3.22-3.34 (1H, m), 3.41 (1H, s) 3.48 (2H, s), 3.60-3.80 (1H,m), 6.27 (1H, d, J=8.0 Hz), 7.24-7.39 (8H, m), 7.54-7.56 (2H, m)

low resolution FAB-MS (m/e, (C₂₅ H₃₀ F₂ N₂ O₂ +H)⁺): 429.

EXAMPLE 17

(2R)-N-[1-(3-fluorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR25##

The title compound was prepared in the same manner as described inExample 15 using 3-fluorobenzyl chloride.

¹ H-NMR (CDCl₃, δ ppm): 1.34-1.52 (2H, m), 1.52-2.30 (10H, m), 2.65-2.80(2H, m), 3.22-3.38 (1H, m), 3.40 (1H, s) 3.72 (2H, s), 3.60-3.80 (1H,m), 6.28 (1H, d, J=7.7 Hz), 6.88-6.97 (1H, m), 7.00-7.10 (2H, m),7.20-7.42 (4H, m), 7.51-7.60 (2H, m)

low resolution FAB-MS (m/e, (C₂₅ H₂₉ F₃ N₂ O₂ +H)⁺): 447.

EXAMPLE 18

(2R)-N-[1-(3-chlorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR26##

The title compound was prepared in the same manner as described inExample 15 using 3-chlorobenzyl chloride.

¹ H-NMR (CDCl₃, δ ppm): 1.33-1.50 (2H, m), 1.60-2.25 (10H, m), 2.67-2.77(2H, m), 3.24-3.38 (1H, m), 3.44 (2H, s) 3.63-3.76 (1H, m), 6.29 (1H, d,J=8.0 Hz), 7.13-7.40 (7H, m), 7.53-7.57 (2H, m)

low resolution FAB-MS (m/e, (C₂₅ H₂₉ ClF₂ N₂ O₂ +H)⁺): 463.

EXAMPLE 19

(2R)-N-[1-(2-thienylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR27##

The title compound was prepared in the same manner as described inExample 15 using 2-thienylmethyl chloride.

¹ H-NMR (CDCl₃, δ ppm): 1.32-1.50 (2H, m), 1.52-2.30 (10H, m), 2.70-2.82(2H, m), 3.22-3.36 (1H, m), 3.41 (1H, s) 3.62-3.76 (1H, m), 3.68 (2H,s), 6.26 (1H, d, J=7.9 Hz), 6.87 (1H, dd, J=3.2 Hz, 4.8 Hz), 6.92 (1H,dd, J=3.2 Hz, 4.8 Hz) 7.21 (1H, dd, J=1.5 Hz, 4.8 Hz), 7.24-7.40 (3H,m), 7.50-7.58 (2H, m)

low resolution FAB-MS (m/e, (C₂₃ H₂₈ F₂ N₂ O₂ S+H)⁺): 435.

EXAMPLE 20

(2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamidedihydrochloride

Structural formula ##STR28##

The compound of Example 20 was prepared by the following methods 1, 2and 3.

Method 1:

Step 1. Synthesis of6-tert-butyldiphenylsilyloxymethylpyridine-2-carboxylic acid

To a solution of 1.8 g of ethyl 6-hydroxymethylpyridine-2-carboxylate in55 ml of N,N-dimethylformamide, 1.4 g of imidazole and 3.9 g oftert-butyldiphenylsilane chloride were added under cooling with ice,sequentially, followed by stirring for 12 hours at room temperature. Thereaction mixture was diluted with ethyl acetate, washed with saturatedsodium bicarbonate solution, water and then brine, and dried overanhydrous magnesium sulfate. Distilling the solvent off under reducedpressure, the residue was dissolved in 60 ml of methanol. To thesolution 7.5 ml of 4N aqueous sodium hydroxide solution was added,stirred for 20 hours at room temperature and for further 2 hours at 60°C. Distilling the methanol off under reduced pressure, the residue wasmade acidic with 1N hydrochloric acid. The system was extracted withchloroform, washed with water and then brine, and dried over anhydrousmagnesium sulfate. Distilling the solvent off under reduced pressure,the resulting residue was purified by silica gel column chromatography(developing solvent: hexane/ethyl acetate=4/1) to provide 895 mg of thetitle compound as a white solid.

Step 2. Synthesis of 6-tert-butyloxycarbonylaminopyridin-2-ylmethyltert-butyldiphenylsilyl ether

To a solution of 890 mg of the6-tert-butyldiphenylsilyloxymethylpyridine-2-carboxylic acid as obtainedin above step 1 in 30 ml of toluene, 0.63 ml of triethylamine, 3.2 ml oftert-butanol and 887 mg of diphenylphosphorylazide were addedsequentially at room temperature, followed by heating for 16 hours at100° C. under stirring. The reaction mixture was diluted with ethylacetate, washed with saturated aqueous sodium bicarbonate solution, 10%aqueous citric acid solution, water and then brine, and dried overanhydrous magnesium sulfate. After the solvent was distilled off underreduced pressure, the resulting residue was purified by silica gelcolumn chromatography (developing solvent: hexane/ethyl acetate=4/1) toprovide 863 mg of the title compound as an oily substance.

Step 3. Synthesis of 6-tert-butyloxycarbonylaminopyridine-2-methanol

The title compound was prepared in the same manner as described in thestep 3 of Example 5 using the6-tert-butyloxycarbonylaminopyridin-2-ylmethyl tert-butyldiphenylsilylether as obtained in above step 2.

Step 4. Synthesis of 6-tert-butyloxycarbonylaminopyridin-2-ylmethylmethanesulfonate

To a solution of 61 mg of the6-tert-butyloxycarbonylaminopyridine-2-methanol as obtained in abovestep 3 in 2 ml of chloroform, 0.19 ml of triethylamine and 0.032 ml ofmethanesulfonyl chloride were added under cooling with ice, followed bystirring for an hour at the same temperature. The reaction liquid wasdiluted with ethyl acetate, washed with saturated aqueous sodiumbicarbonate solution, water and brine by the order stated and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure to give 124 mg of the title compound as an oil.

Step 5. Synthesis of(2R)-N-[1-(6-tert-butyloxycarbonylaminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

The title compound was prepared in the same manner as described inExample 15 using the 6-tert-butyloxycarbonylaminopyridin-2-ylmethylmethanesulfonate as obtained in the step 4 above.

Step 6. Synthesis of(2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

The title compound was obtained as a white solid, upon treating the(2R)-N-[1-(6-tert-butyloxycarbonylaminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclophenyl]-2-hydroxy-2-phenylacetamideas obtained in above step 5 with hydrochloric acid according to usualmanner.

¹ H-NMR (CD₃ OD, δ ppm) 1.76-2.14 (10H, m), 3.20-3.63 (5H, m), 3.85-4.00(1H, m), 4.44 (2H, s), 7.07-7.34 (2H, m), 7.25-7.34 (3H, m), 7.58-7.60(2H, m), 7.89-7.94 (1H, m)

low resolution FAB-MS (m/e, (C₂₄ H₃₀ F₂ N₄ O₂ +H)⁺): 445.

Method 2:

Step 1. Synthesis of ethyl6-tert-butyloxycarbonylaminopyridine-2-carboxylate

The title compound was prepared in the same manner described in the step2 of above method 1, using 6-ethoxycarbonylpyridine-2-carboxylic acid.

Step 2. Synthesis of 6-tert-butyloxycarbonylaminopyridine-2-methanol

To a solution of 500 mg of calcium chloride in 10 ml of ethanol, 150 mgof sodium borohydride was added under cooling with ice, followed bystirring for 15 minutes at the same temperature. To the reaction mixture1.1 g of the ethyl 6-tert-butyloxycarbonylaminopyridine-2-carboxylate asobtained in above step 1 was added and stirred for 13 hours at roomtemperature. The ethanol was distilled off under reduced pressure, andthe residue was suspended in chloroform-water mixture to be removed ofinsoluble material. The organic layer was washed with water and thenbrine and dried over anhydrous magnesium sulfate. Thus 996 mg of thetitle compound was obtained as a light yellow oil.

Step 3. Synthesis of4-tert-butyloxycarbonylamino-1-(6-tert-butyloxycarbonyaminopyridin-2-ylmethyl)piperidine

The title compound was prepared by a method similar to the steps 4 to 5of above production method 1 using the6-tert-butyloxycarbonylaminopyridine-2-methanol as obtained in the abovestep 2 and 4-tert-butyloxycarbonylaminopiperidine.

Step 4. Synthesis of(2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

163 mg of the4-tert-butyloxycarbonyl-amino-1-(6-tert-butyloxycarbonylaminopyridin-2-ylmethyl)piperidineas obtained in above step 3 was dissolved in 5 ml of 10% HCl-methanolsolution, followed by stirring for 13 hours at 40° C. Distilling themethanol off under reduced pressure, the remaining residue was suspendedin 15 ml of chloroform, to which 0.16 ml of triethylamine, 86 mg of(2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid, 114mg of hydroxybenzotriazole and 75 mg of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide were added under coolingwith ice sequentially, followed by stirring for 1.5 hours at roomtemperature. The reaction mixture was diluted with diethyl ether, washedwith saturated aqueous sodium bicarbonate solution and then brine, anddried over anhydrous magnesium sulfate. After the solvent was distilledoff under reduced pressure, the resulting residue was purified by silicagel column chromatography (developing solvent: chloroform/methanol=50/1to 20/1) to obtain 101 mg of the title compound as a white solid.

¹ H-NMR (CDCl₃, δ ppm): 1.35-1.51 (2H, m), 1.70-2.25 (10H, m), 2.68-2.80(2H, m), 3.21-3.35 (1H, m), 3.41 (2H, s), 3.52 (1H, brs), 3.62-3.77 (1H,m), 4.40 (2H, brs), 6.28 (1H, d, J=8.2 Hz), 6.36 (1H, d, J=8.2 Hz), 6.67(1H, d, J=7.3 Hz), 7.27-7.40 (4H, m), 7.53-7.57 (2H, m)

Step 5. Synthesis of(2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamidedihydrochloride

The title compound was prepared by treating the(2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamidewith hydrochloric acid according to the accepted practice.

Method 3:

Step 1. Synthesis of 2-tert-butyloxycarbonylamino-6-methylpyridine

To a solution of 2 g of 6-methyl-2-aminopyridine in 30 ml of chloroform,5 g of di-tert-butyloxydicarbonate was added at room temperature. Thenthe mixture was heated to 70° C., to which 2.5 g of4-dimethylaminopyridine was added, followed by stirring for 2 hours atthe same temperature. After the solvent was distilled off under reducedpressure, the resulting residue was purified by silica gel columnchromatography (developing solvent: hexane/ethyl acetate=20/1) toprovide 4.1 g of the title compound as a white solid.

Step 2. Synthesis of(2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamidedihydrochloride

To a solution of 100 mg of the2-tert-butyloxycarbonylamino-6-methylpyridine as obtained in above step1 in 3 ml of carbon tetrachloride, 90 mg of N-bromosuccinimide and 10 mgof benzoyl peroxide were added sequentially, followed by heating for 6hours under reflux with stirring. Filtering the insoluble materials off,the solvent was distilled off under reduced pressure. The title compoundwas prepared by processing the residue by a method similar to the step 5of method 1 and the steps 4-5 of the method 2.

EXAMPLE 21

(2R)-N-[1-(6-amino-4-methoxypyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamidedihydrochloride

Structural formula ##STR29##

The title compound was prepared by a method similar to Example 20, usingethyl 6-hydroxymethyl-4-methoxypyridine-2-carboxylate.

¹ H-NMR (CD₃ OD, δ ppm): 1.69-2.21 (10H, m), 3.10-3.70 (5H, m),3.83-3.97 (1H, m), 3.98 (3H, s), 4.30-4.46 (2H, m), 6.39-6.47 (1H, m),6.74-6.89 (1H, m), 7.20-7.38 (3H, m), 7.58 (2H, d, J=6.9 Hz)

low resolution FAB-MS (m/e, (C₂₅ H₃₂ F₂ N₄ O₃ +H)⁺): 475.

EXAMPLE 22

(2R)-N-[1-(3-amino-5-methylbenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamidedihydrochloride

Structural formula ##STR30## Step 1. Synthesis ofN-(tert-butyloxycarbonyl)-3,5-dimethylaniline

To a solution of 1.2 g of 3,5-dimethylaniline in a liquid mixture of 20ml of dioxane, 10 ml of 10% aqueous sodium hydroxide solution and 2.7 gof di-tert-butyl-dicarbonate were added, followed by heating for 1.5hours at 100° C. with stirring. The reaction mixture as diluted withdiethyl ether, washed with water and then brine, and dried overanhydrous magnesium sulfate. After the solvent was distilled off underreduced pressure, the resulting residue was purified by silica gelcolumn chromatography (developing solvent: hexane/ethyl acetate=9/1) toprovide 1.8 g of the title compound as an oil.

Step 2. Synthesis of 3-(tert-butyloxycarbonylamino)-5-methylbenzylbromide

To a solution of 1.8 g of theN-(tert-butyloxycarbonyl)-3,5-dimethylaniline as obtained in above step1 in 20 ml of carbon tetrachloride, 1.5 g of N-bromosuccinimide and 53mg of 2,2'-azobis(isobutyronitrile) were added, followed by heating for3 hours at 100° C. under stirring. The reaction mixture was diluted withhexane, filtered and the solvent was distilled off under reducedpressure to provide 2.8 g of the title compound as an oil.

Step 3. Synthesis of(2R)-N-[1-(3-amino-5-methylbenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamidedihydrochloride

The title compound was prepared by a method similar to the steps 5-6 ofthe production method 1 of Example 20, using the3-(tert-butyloxycarbonylamino)-5-methylbenzyl bromide as obtained inabove step 2.

¹ H-NMR (CD₃ OD, δ ppm): 1.66-2.11 (12H, m), 2.99-3.48 (3H, m), 3.26(3H, s), 3.78-3.98 (1H, m), 4.28 (2H, s), 7.18-7.60 (8H, m)

low resolution FAB-MS (m/e, (C₂₆ H₃₃ F₂ N₃ O₂ +H)⁺): 458.

EXAMPLE 23

(2R)-N-[1-(3-aminobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR31## Step 1. Synthesis of(2R)-N-[1-(3-nitrobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

The title compound was prepared by a method similar to Example 15, using3-nitrobenzyl chloride.

Step 2. Synthesis of(2R)-N-[1-(3-aminobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyolopentyl]-2-hydroxy-2-phenylacetamide

6.5 mg of the(2R)-N-[1-(3-nitrobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamideas obtained in above step 1 was heated to 60° C. together with 2 mg ofiron powder in aqueous ethanol. After adding thereto 1 drop of conc.hydrochloric acid, the heating was continued at 100° C. for about 1 hourunder stirring. The reaction mixture was made basic with 4N aqueoussodium hydroxide solution and extracted with chloroform. The organiclayer was dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure to provide 4.8 mg of the titlecompound as a white solid.

¹ H-NMR (CDCl₃, δ ppm) 1.30-1.48 (2H, m), 1.50-2.25 (10H, m), 2.68-2.78(2H, m), 3.24-3.40 (1H, m), 3.38 (2H, s), 3.43 (1H, s), 3.52-3.80 (1H,m), 6.26 (1H, d, J=7.9 Hz), 6.57 (1H, dd, J=1.5 Hz, 7.8 Hz), 6.65 (1H,d, J=1.5 Hz), 6.66 (1H, d, J=7.58 Hz), 7.08 (1H, t, J=7.8 Hz), 7.28-7.39(3H, m), 7.53-7.57 (2H, m)

low resolution FAB-MS (m/e, (C₂₅ H₃₁ F₂ N₃ O₂ +H)⁺): 444.

EXAMPLE 24

(2R)-N-[1-(2-aminobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamidedihydrochloride

Structural formula ##STR32##

The title compound (free base) was obtained by a method similar toExample 23, using 2-nitrobenzyl chloride, which was treated withhydrochloric and to provide the title dihydrochloride compound.

¹ H-NMR (CD₃ OD, δ ppm): 1.50-1.95 (10H, m), 2.92-3.07 (2H, m),3.07-3.20 (1H, m), 3.24-3.38 (2H, m) 3.67-3.80 (1H, m), 4.15-4.27 (2H,m), 7.05-7.45 (9H, m)

low resolution FAB-MS (m/e, (C₂₅ H₃₁ F₂ N₃ O₂ +H)⁺): 444.

EXAMPLE 25

(2R)-N-[1-(4-aminobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR33##

The title compound was prepared by a method similar to Example 23, using4-nitrobenzyl chloride.

¹ H-NMR (CDCl₃, δ ppm): 1.35-1.52 (2H, m), 1.70-2.23 (10H, m), 2.70-2.82(2H, m), 3.23-3.35 (1H, m), 3.41 (2H, s), 3.30-3.70 (3H, m), 3.65-3.75(1H, m), 6.29 (1H, d, J=7.4 Hz), 6.63 (2H, d, J=8.5 Hz), 7.06 (2H, d,J=8.5 Hz), 7.28-7.39 (3H, m), 7.52-7.56 (2H, m)

low resolution FAB-MS (m/e, (C₂₅ H₃₁ F₂ N₃ O₂ +H)⁺): 444.

EXAMPLE 26

(2R)-N-[1-(4-amino-3-methoxybenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR34##

The title compound was prepared by a method similar to Example 23, using3-methoxy-4-nitrobenzyl chloride.

¹ H-NMR (CDCl₃, δ ppm): 1.35-1.60 (2H, m), 1.70-2.30 (10H, m), 2.70-2.90(2H, m), 3.22-3.38 (1H, m), 3.44 (2H, s), 3.40-3.60 (1H, m), 3.62-3.85(3H, m), 3.85 (3H, s), 6.36 (1H, d, J=7.9 Hz), 6.60-6.70 (2H, m), 6.81(1H, s), 7.24-7.40 (3H, m), 7.51-7.58 (2H, m)

low resolution FAB-MS (m/e, (C₂₆ H₃₃ F₂ N₃ O₃ +H)⁺): 474.

EXAMPLE 27

(2R)-N-[1-(3,5-diaminobenzyl)pipieridin-4-yl]-2-[(1R)-33-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR35##

The title compound was prepared by a method similar to Example 23, using3,5-dinitrobenzyl chloride.

¹ H-NMR (CDCl₃, δ ppm): 1.30-2.20 (12H, m), 2.70-2.80 (2H, m), 3.23-3.36(1H, m), 3.28 (2H, s), 3.44 (1H, s), 3.60-3.73 (1H, m), 5.93 (1H, t,J=2.0 Hz), 6.07 (2H, d, J=2.0 Hz), 6.23 (1H, d, J=7.5 Hz), 7.29-7.40(3H, m), 7.53-7.57 (2H, m)

low resolution FAB-MS (m/e, (C₂₅ H₃₂ F₂ N₄ O₂ +H)⁺): 459.

EXAMPLE 28

(2R)-N-[1-(5-methylfuran-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR36## Step 1. Synthesis of4-(tert-butyloxycarbonylamino)-1-(5-methyl-2-furylmethyl)piperidine

To a solution of 200 mg of 4-(tert-butyloxycarbonylamino)piperidine in 5ml of tetrahydrofuran, 0.1 ml of 5-methylfuran-3-aldehyde 0.06 ml ofacetic acid and 318 mg of sodium triacetoxyborohydride were added atroom temperature, followed by stirring for 12 hours. To the reactionmixture, saturated aqueous sodium bicarbonate solution was added and themixture was extracted with ethyl acetate. The organic layer was washedwith brine and dried over anhydrous magnesium sulfate. After distillingthe solvent off under reduced pressure, the residue was recrystallizedfrom ethyl acetate/n-hexane to provide 198 mg of the title compound.

Step 2. Synthesis of(2R)-N-[1-(5-methyl-2-furylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

To 88 mg of the4-(tert-butyloxycarbonylamino)-1-(5-methyl-2-furylmethyl)piperidine asobtained in above step 1, 2 ml of 10% hydrogenchloride solution inmethanol was added at room temperature, followed by stirring for about12 hours. The solvent was distilled off under reduced pressure, and to asolution of the resultant residue in 4 ml of chloroform, 59 mg of(2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid, 93mg of hydroxybenzotriazole, 0.2 ml of triethylamine and 6 mg of1-ethyl-3-(3-dimethylaminopropyl)carbodimide were added sequentially atroom temperature, followed by stirring for 2 hours. After addition ofwater, the reaction mixture was extracted with chloroform. The organiclayer was washed with brine and dried over anhydrous magnesium sulfate.Distilling the solvent off under reduced pressure, the residue waspurified by silica gel column chromatography (developing solvent:chloroform/methanol=50/1) to provide 63 mg of the title compound as awhite solid.

¹ H-NMR (CDCl₃, δ ppm): 1.35-1.54 (2H, m), 1.60-2.25 (10H, m), 2.27 (3H,s), 2.71-2.86 (2H, m), 3.22-3.36 (1H, m), 3.40 (1H, s), 3.45 (2H, s),3.60-3.76 (1H, m), 5.85-5.90 (1H, m), 6.05 (1H, d, J=3.0 Hz), 6.25 (1H,d, J=7.9 Hz), 7.26-7.40 (3H, m), 7.50-7.56 (2H, m)

low resolution FAB-MS (m/e, (C₂₄ H₃₀ F₂ N₂ O₃ +H)⁺): 433.

EXAMPLE 29

(2R)-N-[1-(3-methylbenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR37## Step 1. Synthesis of4-(tert-butyloxycarbonylamino)-1-(3-methylbenzyl)piperidine

The title compound was prepared by a method similar to Example 15, using4-(tert-butyloxycarbonylamino)piperidine and 3-methylbenzyl bromide.

Step 2. Synthesis of(2R)-N-[1-(3-methylbenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

The title compound was prepared by a method similar to Example 28, usingthe 4-(tert-butyloxycarbonylamino)-1-(3-methylbenzyl)piperidine asobtained in above step 1.

¹ H-NMR (CDCl₃, δ ppm): 1.24-1.50 (2H, m), 1.50-2.25 (10H, m), 2.33 (3H,s), 2.60-2.82 (2H, m), 3.20-3.55 (3H, m), 3.42 (2H, s), 6.25 (1H, d,J=8.1 Hz), 7.00-7.14 (3H, m), 7.19 (1H, t, J=7.6 Hz), 7.23-7.42 (3H, m),7.50-7.60 (2H, m)

low resolution FAB-MS (m/e, (C₂₆ H₃₂ F₂ N₂ O₂ +H)⁺) 443.

EXAMPLE 30

(2R)-N-[1-(4-methoxybenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR38##

The title compound was prepared by a method similar to the step 2 ofExample 10, using p-anisaldehyde.

¹ H-NMR (CDCl₃, δ ppm): 1.32-1.47 (2H, m), 1.75-2.23 (10H, m), 2.65-2.76(2H, m), 3.22-3.36 (1H, m), 3.42 (2H, s), 3.46 (1H, s), 3.63-3.76 (1H,m) 3.79 (3H, s), 6.27 (1H, d, J=8.2 Hz), 6.84 (2H, d, J=8.6 Hz), 7.19(2H, d, J=8.6 Hz), 7.28-7.39 (3H, m), 7.52-7.56 (2H, m)

low resolution FAB-MS (m/e, (C₂₆ H₃₂ F₂ N₂ O₃ +H)⁺): 459.

EXAMPLE 31

(2R)-N-[1-(3-amino-5-methoxybenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamidedihydrochloride

Structural formula ##STR39## Step 1. Synthesis of methyl3-tert-butoxycarbonylamino-5-methoxybenzoate

To a solution of 864 mg of methyl 3-methoxy-5-nitrobenzoate in 15 ml ofmethanol, 1.0 g of di-tert-butyl-dicarbonate and 912 mg of 10%palladium-on-carbon were added, followed by stirring for 7 hours at roomtemperature in a hydrogen atmosphere. The reaction liquid was filteredthrough Celite. Distilling the solvent off under reduced pressure, 1.28g of the title compound was obtained as a white solid.

Step 2. Synthesis of 3-tert-butoxycarbonylamino-5-methoxybenzyl alcohol

To a solution of 1.28 mg of the methyl3-tert-butoxycarbonylamino-5-methoxybenzoate as obtained in above step 1in 8 ml of toluene, 12.1 ml of 1.0 M solution of diisobutylaluminumhydride in tetrahydrofuran was added at -78° C., followed by stirringfor an hour at the same temperature. The reaction mixture was dilutedwith ethyl acetate, washed with water and then brine and dried overanhydrous magnesium sulfate. After distilling the solvent off underreduced pressure, the resulting residue was purified by silica gelcolumn chromatography (developing solvent: hexane/ethyl acetate=7/3) toprovide 262 mg of the title compound as an oil.

Step 3. Synthesis of 3-tert-butoxycarbonylamino-5-methoxybenzaldehyde

To a solution of 194 mg of the3-tert-butoxycarbonylamino-5-methoxybenzyl alcohol as obtained in abovestep 2 in 10 ml of chloroform, 1.89 g of manganese dioxide was added atroom temperature, followed by stirring for 2 hours. The reaction mixturewas filtered through Celite. Distilling the solvent off under reducedpressure, 132 mg of the title compound was obtained as an oilysubstance.

Step 4. Synthesis of(2R)-N-[1-(3-amino-5-methoxybenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamidedihydrochloride

The title compound was prepared by a method similar to the step 2 ofExample 10 and the step 6 of method 1 of Example 20, using the3-tert-butoxycarbonylamino-5-methoxybenzaldehyde as obtained in abovestep 3.

¹ H-NMR (CD₃ OD, δ ppm): 1.74-2.14 (10H, m), 3.00-3.15 (2H, m),3.27-3.52 (3H, m), 3.82-3.92 (1H, m), 3.89 (3H, s) 4.32 (2H, s), 7.01(1H, s), 7.18-7.35 (5H, m), 7.56-7.60 (2H, m)

low resolution FAB-MS (m/e. (C₂₆ H₃₃ F₂ N₃ O₃ +H)⁺): 474.

EXAMPLE 32

(2R)-N-[1-(4-amino-3-fluorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR40##

The title compound was prepared by a method similar to Example 22, using3-fluoro-4-aminotoluene.

¹ H-NMR (CDCl₃, δ ppm) 1.28-1.50 (2H, m), 1.50-2.32 (10H, m), 2.60-2.80(2H, m), 3.20-3.38 (1H, m), 3.33 (2H, s), 3.45 (1H, s), 3.55-3.76 (3H,m), 6.25 (1H, d, J=8.2 Hz), 6.69 (1H, dd, J=8.1, 8.9 Hz), 6.82 (1H, dd,J=1.6, 8.1 Hz), 6.93 (1H, dd, J=1.6, 12.0 Hz), 7.24-7.40 (3H, m),7.50-7.58 (2H, m)

low resolution FAB-MS (m/e, (C₂₅ H₃₀ F₃ N₃ O₂ +H)⁺): 462.

EXAMPLE 33

(2R)-N-[1-(6-amino-4-methylpyridin-2-yl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR41## Step 1. Synthesis of6-chloromethyl-4-methyl-2-acetylaminopyridine

To a solution of 23 mg of 6-acetylamino-4-methylpyridine-2-methanol in 2ml of chloroform, 0.05 ml of thionyl chloride was added at roomtemperature, followed by heating for 15 minutes with stirring underreflux. Distilling the solvent off under reduced pressure, the titlecompound was obtained.

Step 2. Synthesis of(2R)-N-[1-(6-acetylamino-4-methylpyridin-2-yl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

The title compound was prepared by a method similar to Example 15, usingthe 6-chloromethyl-4-methyl-2-acetylaminopyridine as obtained in abovestep 1.

Step 3. Synthesis of(2R)-N-[1-(6-amino-4-methylpyridin-2-yl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

To a solution of 16.5 mg of the(2R)-N-[1-(6-acetylamino-4-methylpyridin-2-yl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamideas obtained in above step 2 in 1 ml of methanol, 0.5 ml of 3M aqueoussodium hydroxide solution was added, and stirred for 1.5 hours at 60° C.The reaction liquid was diluted with diethyl ether, washed with waterand brine by the order stated and dried over anhydrous magnesiumsulfate. Distilling the solvent off under reduced pressure, theresulting residue was purified by preparative thin-layer chromatography[Kieselgel™ 60F₂₅₄, Art 5744 (Merck); developing solvent:chloroform/methanol=10/1) to provide 14 mg of the title compound as anoily substance.

¹ H-NMR (CDCl₃, δ ppm) 1.30-1.50 (2H, m), 1.71-2.30 (10H, m), 2.33 (3H,s), 2.62-2.76 (2H, m), 3.21-3.38 (1H, m), 3.29 (2H, s), 3.60-3.78 (1H,m), 4.35-4.51 (2H, m), 6.26 (1H, s), 6.35 (1H, d, J=8.1 Hz), 6.45 (1H,s), 7.25-7.40 (3H, m), 7.52-7.60 (2H, m)

low resolution FAB-MS (m/e, (C₂₅ H₃₂ F₂ N₄ O₂ +H)⁺) 459.

EXAMPLE 34

(2R)-N-[1-(3-amino-4-fluorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamidedihydrochloride

Structural formula ##STR42##

The title compound was prepared by a method similar to Example 22, using2-fluoro-5-methylaniline.

¹ H-NMR (CD₃ OD, δ ppm) 1.68-2.11 (10H, m), 3.00-3.50 (5H, m), 3.79-3.90(1H, m), 4.32 (2H, s), 7.18-7.30 (3H, m), 7.43 (1H, d, J=8.4 Hz),7.52-7.56 (2H, m), 7.57-7.65 (1H, m), 7.73-7.78 (1H, m)

low resolution FAB-MS (m/e, (C₂₅ H₃₀ F₃ N₃ O₂ +H)⁺): 462.

EXAMPLE 35

(2R)-N-[1-(5-amino-2-fluorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR43##

The title compound was prepared by a method similar to the step 2 ofExample 22 and Example 23, using 2-fluoro-5-nitrotoluene.

¹ H-NMR (CDCl₃, δ ppm) 1.36-1.49 (2H, m), 1.57-2.26 (10H, m), 2.71-2.78(2H, m), 3.24-3.36 (1H, m), 3.42-3.57 (5H, m), 3.66-3.75 (1H, m), 6.24(1H, d, J=8.1 Hz), 6.51-6.56 (1H, m), 6.65-6.68 (1H, m), 6.82 (1H, t,J=9.0 Hz), 7.29-7.40 (3H, m) 7.53-7.57 (2H, m)

low resolution FAB-MS (m/e, (C₂₅ H₃₀ F₃ N₃ O₂ +H)⁺): 462.

EXAMPLE 36

(2R)-N-[1-(2-amino-4-chloropyridin-6-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR44##

The title compound was prepared by a method similar to method 2 ofExample 20, using methyl 4-chloro-6-hydroxymethylpyridine-2-carboxylate.

¹ H-NMR (CDCl₃, δ ppm): 1.42-1.54 (2H, m), 1.78-2.26 (10H, m), 2.76-2.79(2H, m), 3.28-3.38 (1H, m), 3.42-3.47 (3H, m), 3.67-3.75 (1H, m),4.53-4.56 (2H, m), 6.36 (1H, d, J=7.2 Hz), 6.38 (1H, d, J=1.6 Hz), 6.72(1H, d, J=1.6 Hz), 7.25-7.39 (3H, m), 7.53-7.57 (2H, m)

low resolution FAB-MS (m/e, (C₂₄ H₂₉ ClF₂ N₄ O₂ +H)⁺): 479.

EXAMPLE 37

(2R)-N-[1-(3-amino-5-chlorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR45## Step 1. Synthesis of 3-chloro-5-nitrobenzylmethanesulfonate

To a solution of 92 mg of 3-chloro-5-nitrobenzyl alcohol in 3 ml ofchloroform, 0.3 ml of triethylamine and 0.1 ml of methanesulfonylchloride were added at room temperature, followed by stirring for 40minutes, addition of saturated aqueous sodium bicarbonate solution andfurther stirring for 30 minutes. The reaction mixture was diluted withdiethyl ether, washed with saturated aqueous sodium bicarbonate solutionand then brine and dried over anhydrous magnesium sulfate. Distillingthe solvent off under reduced pressure, 119 mg of the title compound wasobtained as an oil.

Step 2. Synthesis of(2R)-N-[1-(3-amino-5-chlorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

The title compound was obtained by a method similar to Example 23, usingthe 3-chloro-5-nitrobenzyl methanesulfonate as obtained in above step 1.

¹ H-NMR (CDCl₃, δ ppm): 1.30-1.44 (2H, m), 1.73-2.22 (10H, m), 2.68-2.73(2H, m), 3.24-3.36 (1H, m), 3.32 (2H, s), 3.44 (1H, brs), 3.61-3.77 (3H,m), 6.28 (1H, d, J=8.4 Hz), 6.49 (1H, d, J=1.9 Hz), 6.55 (1H, dd, J=1.7,1.9 Hz), 6.66 (1H, d, J=1.7 Hz), 7.29-7.39 (3H, m), 7.53-7.56 (2H, m)

low resolution FAB-MS (m/e, (C₂₅ H₃₀ ClF₂ N₃ O₂ +H)⁺): 459.

EXAMPLE 38

(2R)-N-[1-(4-amino-3,5-difluorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR46##

The title compound was prepared by a method similar to the step 2 ofExample 10, using 4-amino-3,5-difluorobenzaldehyde.

¹ H-NMR (CDCl₃, δ ppm): 1.24-2.22 (12H, m), 2.66-2.72 (2H, m), 3.27-3.41(4H, m), 3.66-3.71 (3H, m), 6.28 (1H, d, J=7.8 Hz), 6.77 (2H, d, J=8.3Hz), 7.28-7.39 (3H, m), 7.54-7.56 (2H, m)

low resolution FAB-MS (m/e, (C₂₅ H₂₉ F₄ N₃ O₂ +H)⁺) 480.

EXAMPLE 39

(2R)-N-[1-(benzimidazol-5-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

Structural formula ##STR47##

The title compound was prepared by a method similar to the step 2 ofExample 10, using benzimidazole-5-carbaldehyde.

¹ -H-NMR (CD₃ OD, δ ppm): 1.45-2.25 (10H, m), 2.25-2.48 (2H, m),2.90-3.10 (2H, m), 3.20-3.42 (1H, m), 3.56-3.75 (1H, m), 3.82 (2H, s),7.18-7.40 (4H, m), 7.51-7.75 (4H, m), 8.17 (1H, s)

low resolution FAB-MS (m/e, (C₂₆ H₃₀ F₂ N₄ O₂ +H)⁺): 469.

EXAMPLE 40

(2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-(3,3-difluorocyclobutyl)-2-hydroxy-2-phenylacetamide

Structural formula ##STR48##

The title compound was prepared by a method similar to the step 4 ofmethod 2 of Example 20, using(2R)-(3,3-difluorocyclobutyl)-2-hydroxyphenylacetic acid and4-amino-1-(6-aminopyridin-2-ylmethyl)piperidine trihydrochloride.

¹ H-NMR (CDCl₃, δ ppm): 1.20-1.52 (2H, m), 1.60-1.86 (2H, m), 2.08-2.22(2H, m), 2.40-2.82 (6H, m), 3.07-3.21 (1H, m), 3.41 (2H, s), 3.60-3.80(1H, m), 3.84 (1H, brs), 4.40 (2H, brs), 6.01 (1H, d, J=8.1 Hz), 6.36(1H, d, J=8.2 Hz), 6.66 (1H, d, J=8.2 Hz), 7.28-7.42 (4H, m), 7.43-7.50(2H, m)

low resolution FAB-MS (m/e, (C₂₃ H₂₈ F₂ N₄ O₂ +H)⁺) 431.

EXAMPLE 41

(2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-(4,4-difluorocyclohexyl)-2-hydroxy-2-phenylacetamide

Structural formula ##STR49##

The title compound was prepared by a method similar to the step 4 ofmethod 2 of Example 20, using(2R)-(4,4-difluorocyclohexyl)-2-hydroxyphenylacetic acid and4-amino-1-(6-aminopyridin-2-ylmethyl)piperidine trihydrochloride.

¹ H-NMR (CDCl₃, δ ppm): 1.20-1.97 (10H, m), 1.97-2.22 (4H, m), 2.44-2.68(1H, m), 2.70-2.92 (3H, m), 3.42 (2H, s), 3.62-3.80 (1H, m), 4.42 (2H,brs), 6.36 (1H, d, J=8.2 Hz), 6.62 (1H, d, J=7.9 Hz), 6.67 (1H, d, J=8.2Hz), 7.24-7.42 (4H, m), 7.55-7.62 (2H, m)

low resolution FAB-MS (m/e, (C₂₅ H₃₂ F₂ N₄ O₂ +H)⁺): 459.

EXAMPLE 42

(2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-(3,3-difluorocyclopentyl)-2-(4-fluorophenyl)-2-hydroxyacetamide

Structural formula ##STR50##

The title compound was prepared by a method similar to the method 1 ofExample 20, using(2R)-(3,3-difluorocyclopentyl)-2-(4-fluorophenyl)-2-hydroxyacetic acid.

¹ H-NMR (CDCl₃, δ ppm): 1.39-1.55 (2H, m), 1.70-2.22 (10H, m), 2.73-2.81(2H, m), 3.23-3.36 (1H, m), 3.43 (2H, s), 3.65-3.77 (1H, m), 4.43 (2H,brs), 6.31 (1H, d, J=7.6 Hz), 6.37 (1H, d, J=8.2 Hz) 6.67 (1H, d, J=7.4Hz), 7.01-7.08 (2H, m), 7.37 (1H, dd, J=7.4, 8.2 Hz), 7.51-7.58 (2H, m)

low resolution FAB-MS (m/e, (C₂₄ H₂₉ F₃ N₄ O₂ +H)⁺): 463.

REFERENTIAL EXAMPLE 1

(2R)-[(1R)-3-oxocyclopentyl]-2-hydroxy-2-phenylacetic acid

Step 1. Synthesis of(2R,5R)-2-(t-butyl)-5-[(1R)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-oneand (2R,5R)-2-(t-butyl)-5-[(1S)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one

To a mixture of 510 mg of(2R,5R)-2-(t-butyl)-5-phenyl-1,3-dioxolan-4-one-which had beensynthesized by the method of D. Seebach, et al. [Tetrahedron. Vol. 40,pp. 1313-1324 (1984)] in 20 ml of tetrahydrofuran and 1 ml ofhexamethylphosphoric triamide, 1.7 ml of 1.5M lithium diisopropylamidesolution in hexane was added dropwise at -78° C., followed by stirringfor 30 minutes. Then a solution of 285 mg of cyclopentenone in 1.5 ml oftetrahydrofuran was added, and the reaction mixture was stirred for 1.5hours. The reaction mixture was diluted with ethyl acetate, washed withsaturated aqueous ammonium chloride solution, water and then brine, anddried over anhydrous magnesium sulfate. Distilling the solvent off underreduced pressure, resulting residue was purified by medium pressuresilica gel column chromatography (developing solvent: hexane/ethylacetate=15/1-10/1). Thus 150 mg and 254 mg, respectively, of the titlecompounds were obtained as oil. Configuration of each of the compoundswas determined from NOE of NMR.

Step 2. Synthesis of(2R)-[(1R)-3-oxocyclopentyl]-2-hydroxy-2-phenylacetic acid

To a solution of 61 mg of(2R,5R)-2-(t-butyl)-5-[(1R)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-onein 3 ml of methanol, 1 ml of 1N aqueous sodium hydroxide solution wasadded, followed by stirring for 3 hours at room temperature. Distillingthe methanol off under reduced pressure, the residue was diluted withwater and washed with diethyl ether. The aqueous layer was made acidicwith 1N hydrochloric acid and extracted with diethyl ether. The organiclayer was dried over anhydrous magnesium sulfate to provide 48 mg of thetitle compound.

REFERENTIAL EXAMPLE 2

(2R)-[(1S)-3-oxocyclopentyl]-2-hydroxy-2-phenylacetic acid

The title compound was prepared by a method similar to the step 2 ofReferential Example 1, using(2R,5R)-2-(t-butyl)-5-[(1S)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one.

REFERENTIAL EXAMPLE 3

(2R)-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid

Step 1. Synthesis of(2R,5R)-2-(t-butyl)-5-[(1R)-3,3-difluorocyclopentyl]-5-phenyl-1,3-dioxolan-4-one

To a solution of 256 mg of(2R,5R)-2-(t-butyl)-5-[(1R)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-onein 3 ml of chloroform, 0.34 ml of diethylaminosulfurtrifluoride wasadded under cooling with ice, followed by stirring for 20 hours at roomtemperature. The reaction mixture was diluted with diethyl ether, washedwith water and then brine, and dried over anhydrous magnesium sulfate.Distilling the solvent off under reduced pressure, resulting residue waspurified by silica gel column chromatography (developing solvent:hexane/ethyl acetate=20/1) to provide 115 mg of the title compound.

Step 2. Synthesis of(2R)-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid

The title compound was prepared by a method similar to the step 2 ofReferential Example 1, using(2R,5R)-2-(t-butyl)-5-[(1R)-3,3-difluorocyclopentyl]-5-phenyl-1,3-dioxolan-4-one.

REFERENTIAL EXAMPLE 4

(2R)-[(1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid

The title compound was prepared by a method similar to ReferentialExample 3, using(2R,5R)-2-(t-butyl)-5-[(1S)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one.

REFERENTIAL EXAMPLE 5

(2R)-[(1S)-3-hydroxycyclopentyl]-2-hydroxy-2-phenylacetic acid

Step 1. Synthesis of(2R,5R)-2-(t-butyl)-5-[(1S)-3-hydroxycyclopentyl]-5-phenyl-1,3-dioxolan-4-one

To a solution of 169 mg of(2R,5R)-2-(t-butyl)-5-[(1S)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-onein 2 ml of methanol, 71 mg of sodium borohydride was added under coolingwith ice, followed by stirring for 30 minutes at the same temperature.The reaction mixture was diluted with diethyl ether, washed with waterand then brine, and dried over anhydrous magnesium sulfate. Distillingthe solvent off under reduced pressure, 157 mg of the title compound wasobtained as a colorless oil.

Step 2. Synthesis of(2R)-[(1S)-3-hydroxycyclopentyl]-2-hydroxy-2-phenylacetic acid

The title compound was prepared by a method similar to the step 2 ofReferential Example 1, using(2R,5R)-2-(t-butyl)-5-[(1S)-3-hydroxycyclopentyl]-5-phenyl-1,3-dioxolan-4-one.

REFERENTIAL EXAMPLE 6

(2R)-[(1R)-3-hydroxycylopentyl]-2-hydroxy-2-phenylacetic acid

The title compound was prepared by a method similar to ReferentialExample 5, using(2R,5R)-2-(t-butyl)-5-[(1R)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one.

REFERENTIAL EXAMPLE 7

(2R)-[(1S)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetic acid

The title compound was prepared by a method similar to ReferentialExample 3, using(2R)-[(1S)-3-hydroxycyclopentyl]-2-hydroxy-2-phenylacetic acid.

REFERENTIAL EXAMPLE 8

(2R)-[(1R)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetic acid

The title compound was prepared by a method similar to ReferentialExample 3, using(2R)-[(1R)-3-hydroxycyclopentyl]-2-hydroxy-2-phenylacetic acid.

REFERENTIAL EXAMPLE 9

2-cyclopentyl-2-hydroxy-2-phenylacetic acid

To a solution of 23.5 g of ethyl phenylglyoxylate in 200 ml oftetrahydrofuran, 70 ml of 2.0 M cyclopentylmagnesium chloride solutionin diethyl ether was added dropwise under cooling with ice, followed bystirring for 30 minutes at the same temperature. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous ammoniumchloride solution and brine, and dried over anhydrous magnesium sulfate.Distilling the solvent off under reduced pressure, the residue waspurified by silica gel column chromatography (developing solvent:hexane/ethyl acetate=30/1-20/1) to provide 11 g of ethyl2-cyclopentyl-2-hydroxy-2-phenylacetate, which was dissolved in 40 ml ofmethanol. To the solution 20 ml of 4N aqueous sodium hydroxide solutionwas added at room temperature, followed by stirring for 2 hours at thesame temperature and further for 1 hour at 50° C. Distilling themethanol off under reduced pressure, the aqueous layer was made weaklyacidic with 4N hydrochloric acid and extracted with ethyl acetate. Theorganic layer was washed with water and then brine and dried overanhydrous magnesium sulfate. Distilling the solvent off under reducedpressure, the residue was washed with 1:1 mixture of diethyl ether andhexane. Thus, 8.7 g of the title compound was obtained.

REFERENTIAL EXAMPLE 10

(2R)-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid

Step 1. Synthesis of (2R,5R)-2-(t-butyl)-5-[(1S,2R,5R,6S,7R)-3-oxotricyclo[5.2.1.0².6]dec-8-en-5-yl]-5-phenyl-1,3-dioxolan-4-one

To a solution of 32 g of (2R,5R)-2-(t-butyl)-5-phenyl-1,3-dioxolan-4-onein 1.1 l of tetrahydrofuran, 105 ml of 1.5 M lithium diisopropylamidesolution in hexane was added dropwise at -78° C., followed by stirringfor 30 minutes, addition of 23.4 g of (1S,2R,6S,7R)-tricyclo[5.2.1.0².6]dec-4,8-dien-3-one as dissolved in 300 ml of tetrahydrofuran, andfurther stirring for 1.5 hours. The reaction mixture was diluted withethyl acetate, washed with saturated aqueous ammonium chloride solution,water and then brine, and dried over anhydrous magnesium sulfate.Distilling the solvent off under reduced pressure, the residue wasrecrystallized from hexane-ethyl acetate. Thus 36.9 g of the titlecompound was obtained as a white solid.

Step 2. Synthesis of(2R,5R)-2-(t-butyl)-5-[(1S)-4-oxo-2-cyclopentenyl]-5-phenyl-1,3-dioxolan-4-one

A solution of 25.6 g of the(2R,5R)-2-(t-butyl)-5-[(1S,2R,5R,6S,7R)-3-oxo-8-tricyclo [5.2.1.0².6]-dec-8-en-5-yl]-5-phenyl-1,3-dioxolan-4-one as obtained in above step 1in 350 ml of 1,2-dichlorobenzene was heated at 175° C. for 7 hours withstirring, under nitrogen atmosphere. Thus precipitated solid wasrecovered by filtration and washed with hexane to provide 14 g of thetitle compound as a white solid.

Step 3. Synthesis of(2R,5R)-2-(t-butyl)-5-[(1R)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one

To a solution of 19.1 g of the(2R,5R)-2-(t-butyl)-5-[(1S)-4-oxo-2-cyclopentenyl]-5-phenyl-1,3-dioxolan-4-oneas obtained in above step 2 in 700 ml of ethyl acetate, 2.0 g of 10%palladium-on-carbon was added, followed by stirring for 2 hours at roomtemperature under hydrogen atmosphere. Filtering the catalyst off thendistilling the solvent off under reduced pressure, the residue wasrecrystallized from hexane-ethyl acetate to provide 14 g of the titlecompound as a white solid.

Step 4. Synthesis of(2R)-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid

The title compound was prepared by a method similar to ReferentialExample 3, using the(2R,5R)-2-(t-butyl)-5-[(1R)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-oneas obtained in above step 3.

REFERENTIAL EXAMPLE 11

(2R)-(3,3-difluorocyclopentyl)-2-(4-fluorophenyl)-2-hydroxyacetic acid

The title compound was prepared by a method similar to the step 1 ofReferential Example 1 and Referential Example 3, using(R)-4-fluoromandelic acid.

REFERENTIAL EXAMPLE 12

(2R)-(3,3-difluorocyclobutyl)-2-hydroxy-2-phenylacetic acid

Step 1. Synthesis of(2R,5R)-2-(t-butyl)-5-(3-benzyloxy-1-hydroxycyclobutyl)-5-phenyl-1,3-dioxolan-4-one

The title compound was prepared by a method similar to the step 1 ofReferential Example 1, using 3-benzyloxycyclobutanone.

Step 2. Synthesis of(2R,5R)-2-(t-butyl)-5-(3-benzyloxycyclobutyl)-5-phenyl-1,3-dioxolan-4-one

To a solution of 2.82 g of the(2R,5R)-2-(t-butyl)-5-(3-benzyloxy-1-hydroxycyclobutyl)-5-phenyl-1,3-dioxolan-4-oneas obtained in above step 1 in 80 ml of chloroform, 2.6 g of4-dimethylaminopyridine was added under cooling with ice, followed bystirring for an hour at the same temperature. To the reaction mixture, 1ml of methyl chloroglyoxylate was added, followed by stirring for anhour. The reaction mixture was diluted with chloroform, washed withwater and then brine, and dried over anhydrous magnesium sulfate.Distilling the solvent off under reduced pressure, the residue was mixedwith hexane/ethyl acetate=1/1 liquid mixture and filtered through asilica gel column. Distilling the solvent off under reduced pressure,the residue was dissolved in 80 ml of toluene, and to the solution 56 mgof 2,2'-azobis(isobutyronitrile) and 2.3 ml of tri-n-butyltin hydridewere added, followed by heating for 4 hours at 110° C. with stirring.Distilling the solvent off under reduced pressure, the residue waspurified by silica gel column chromatography (developing solvent:hexane/ethyl acetate=8/1) to provide 1.82 g of the title compound as anoily substance.

Step 3. Synthesis of(2R,5R)-2-(t-butyl)-5-(3-oxocyclobutyl)-5-phenyl-1,3-dioxolan-4-one

To a solution of 1.82 g of the(2R,5R)-2-(t-butyl)-5-(3-benzyloxycyclobutyl)-5-phenyl-1,3-dioxolan-4-oneas obtained in above step 2 in 40 ml of ethanol. 430 mg of palladiumhydroxide-carbon was added, followed by stirring for 6 hours at roomtemperature under hydrogen atmosphere. The reaction mixture was filteredthrough Celite. Distilling the solvent off under reduced pressure, theresidue was dissolved in 5 ml of dichloromethane, and the resultingsolution was added dropwise at -78° C. to a reaction mixture formed byadding 0.63 ml of oxalyl chloride to 1.1 ml of dimethylsulfoxide in 50ml of dichloromethane at -78° C. and stirring for 5 minutes. Afterstirring for 15 minutes at the same temperature, 0.5 ml of triethylaminewas added to the reaction mixture and stirred for 30 minutes whileraising the temperature to room temperature. The reaction liquid wasdiluted with chloroform, washed with water and then brine, and driedover anhydrous magnesium sulfate. Distilling the solvent off underreduced pressure, the residue was purified by silica gel columnchromatography (developing solvent: hexane/ethyl acetate=8/1) to provide1.36 g of the title compound as an oily substance.

Step 4. Synthesis of(2R)-(3,3-difluorocyclobutyl)-2-hydroxy-2-phenylacetic acid

The title compound was prepared by a method similar to ReferentialExample 3, using the(2R,5R)-2-(t-butyl)-5-(3-oxocyclobutyl)-5-phenyl-1,3-dioxolan-4-one asobtained in above step 3.

REFERENTIAL EXAMPLE 13

(2R)-(4,4-difluorocyclohexyl)-2-hydroxy-2-phenylacetic acid

Step 1. Synthesis of(2R,5R)-2-(t-butyl)-5-(1,4-dioxaspiro[4.5]-dec-8-yl)-5-phenyl-1,3-dioxolan-4-one

The title compound was prepared by a method similar to the steps 1 and 2of Referential Example 12, using 1,4-dioxa-8-oxospiro[4.5]decane.

Step 2. Synthesis of(2R,5R)-2-(t-butyl)-5-(4-oxocyclohexyl)-5-phenyl-1,3-dioxolan-4-one

To a solution of 83 mg of the(2R,5R)-2-(t-butyl)-5-(1,4-dixoaspiro[4.5]dec-8-yl)-5-phenyl-1,3-dioxolan-4-onein a mixture of 4 ml of acetone and 0.4 ml of water, 52 mg ofp-toluenesulfonic acid was added at room temperature, followed bystirring for 13 hours at 50° C. Distilling the acetone off under reducedpressure, the residue was diluted with ethyl acetate, washed withsaturated aqueous sodium bicarbonate solution and then brine, and driedover anhydrous magnesium sulfate. Distilling the solvent off underreduced pressure, 70 mg of the title compound was obtained as an oil.

Step 3. Synthesis of (2R)-(4,4-difluorocyclohexyl)-2-hydroxyphenylaceticacid

The title compound was prepared by a method similar to ReferentialExample 3, using the(2R,5R)-2-(t-butyl)-5-(4-oxocyclohexyl)-5-phenyl-1,3-dioxolan-4-one.

REFERENTIAL EXAMPLE 14

(2R)-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid

Step 1. Synthesis of(2R,5R)-2-(t-butyl)-5-[(1R)-3-hydroxyiminocyclopentyl]-5-phenyl-1,3-dioxolan-4-one

To a solution of 46 mg of(2R,5R)-2-(t-butyl)-5-[(1R)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-onein 1.5 ml of pyridine, 85 mg of hydroxylamine hydrochloride was addedand the mixture was stirred for 1 hour at room temperature. The reactionmixture was diluted with ethyl acetate and washed with water and brine,and then dried over anhydrous sodium sulfate. The solvent was removedunder reduced pressure to give 55 mg of the title compound.

Step 2. Synthesis of(2R,5R)-2-(t-butyl)-5-[(1R)-3,3-difluorocyclopentyl]-5-phenyl-1,3-dioxolan-4-one

To a mixture of 20 mg of nitrosonium tetrafluoro borate and 0.5 ml of70% hydrogen fluoride-pyridine, a solution of 34 mg of(2R,5R)-2-(t-butyl)-5-[(1R)-3-hydroxyiminocyclopentyl]-5-phenyl-1,3-dioxolan-4-onein 0.5 ml of dichloromethane was added under ice-cooling. The mixturewas stirred for 10 minutes at 0° C. and 5 hours at room temperature.Water was added to the reaction mixture under ice-cooling and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated aqueous sodium bicarbonate solution and then brine, anddried over anhydrous magnesium sulfate. The solvent was removed underreduced pressure to give 35 mg of the title compound.

Step 3. (2R)-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylaceticacid

The title compound was prepared by a method similar to the step 2 ofReferential Example 1, using(2R,5R)-2-(t-butyl)-5-[(1R)-3,3-difluorocyclopentyl]-5-phenyl-1,3-dioxolan-4-one.

Industrially utilizability

The fluorine-containing 1,4-disubstituted piperidine derivatives of thepresent invention have not only potent selective antagonistic activityfor muscarinic M₃ receptors but also little side effect. Furthermorethey exhibit excellent oral activity, duration of action andpharmacokinetics. Hence, they are very useful in the treatment orprophylaxis of diseases such respiratory diseases as chronic obstructivepulmonary diseases, chronic bronchitis, asthma and rhinitis: digestivediseases such as irritable bowel syndrome, convulsive colitis,diverticulitis and pain accompanying contraction of smooth muscles ofthe digestive system: urinary disorders like urinary incontinence andfrequency in neurogenic pollakiurea, neurogenic bladder, nocturnalenuresis, unstable bladder, cystospasm and chronic cystisis: and motionsickness.

We claim:
 1. 4-Amino-1-(6-aminopyridin-2-ylmethyl) piperidine or a saltthereof.
 2. The compound according to claim 1 wherein the salt istrihydrochloride.